Treatment of demyelinating disorders
This invention is directed to pharmaceutical compositions and methods for treating demyelinating disorders based upon inhibitors of the interaction of glutamate with the AMPA and of the interaction of glutamate with the kainate receptor complex.
[0001] The present invention relates inter alia to the treatment of demyelinating disorders.
[0002] The majority of excitatory synaptic responses in mammalian CNS are elicited by amino acids such as L-glutamate or L-aspartate and are mediated by four different receptor subtypes. Three of these receptors are coupled to ionophores and are known as the N-methyl-D-aspartate (NMDA), the AMPA &agr;-amino-3-hydroxy-5-methyl-4-isoxazole-propionate), and the kainate receptors. Typically these receptors will be in the form of a receptor complex including for example glutamate and/or agonist binding site(s), modulatory site(s) and an ion channel, and possibly also including other moieties interacting with the function of the channel. The fourth receptor subtype is linked to phosphoinositol metabolism and is known as the metabotropic glutamate receptor.
[0003] The NMDA receptor is coupled to high conductance channels permeable to Na+, K+, and Ca2+ (McBain C J, Mayer M (1994): N-Methyl-D-aspartic acid receptor structure and function, Physiol. Rev., 74:723-760). It is modulated by glycine (coagonist) and polyamines (positive modulator) and is blocked in a use- and voltage dependent manner by Mg2+. The functional NMDA receptor is thought to be formed as a pentameric subunit assembly consisting of subunit selection from NR1 (eight isoforms) and NR2 (four isoforms) families (Hollmann M, Heinemann S (1994): Cloned glutamate receptors, Annu. Rev. Neurosci. 17:31-108). The type of subunits forming the NMDA channel determine its biophysical properties and physiological function (Schbpfer R, Monyer H, Sommer B, Wisden W, Sprengel R, Kuner T, Lomeli H, Herb A, Kohler M, Butnashev N (1994): Molecular biology of glutamate receptors, Prog. Neurobiol. 42:353-357). The AMPA and kainate receptors are permeable to Na+ and K+ (Hollmann and Heinemann, 1994 [supra]). AMPA receptor-dependent ion channel is formed from four different subunits designated as GluR1 to GluR4 (in two alternative splice variants—flip and flop) in a tetrameric subunit assembly (Hollmann and Heinemann, 1994 [supra]; Rosenmund C, Stern-Bach Y, Stevens C (1998): The tetrameric structure of a glutamate receptor channel, Science 280:1596-1599). Pharmacological properties of AMPA receptor-dependent ion channels are determined by the selection of subunits. Channel assemblies lacking GluR2 subunits are permeable to Ca2+ in addition to Na+- and K+-permeability (Hollmann and Heinemann, 1994 [supra]). In situ hybridization has revealed different expression of glutamate receptor subunits throughout the brain and during development (Monyer H, Burnashev N, Laurie D J, Sakmann B, Seeburg P (1994): Developmental and regional expression in the rat brain and functional properties of four NMDA receptors, Neuron 12:529-540).
[0004] Kainate receptors represent the third type of ionotropic glutamate receptors (E. A.
[0005] Barnard, Ionotropic glutamate receptors: new types and new concepts. Trends Pharmacol. Sci. 18: 141-148, 1997). The kainate receptors are formed heterometrically by GluR5-7 and KA1-2 types of subunits (Y. Paas, The macro- and microarchitectures of the ligand-binding domain of glutamate receptors. Trends in Neurosci. 21, 117-125, 1998). By being activated (opened) and desensitized (closed) by glutamate, kainate receptors modulate a passive flow of Na+, K+ and to varying degree, Ca2+ ions across the cell membrane. As such kainate receptors mediate fast synaptic transmission in the nervous system and are involved in plasticity, transmission of sensory signals and in development (E. A. Barnard, ibid). Furthermore, kainate receptors are unevenly distributed in the brain and spinal cord of rodents and primates (J. M. Henley, Trends Pharmacol. Sci. 15, 182-190, 1994).
[0006] Dysfunction of kainate receptors may contribute to pathogenesis of variety of neurological and psychiatric disorders (B. Meldrum and J. Garthwaite, Trends Pharmacol. Sci. 11, 379-387, 1990).
[0007] In contrast to the well documented role of glutamate in the pathogenesis of neuronal degeneration resulting from hypoxia/ischemia, hypoglycemia, convulsions and head or spinal cord trauma, no clear link has been established between glutamate-mediated cell death and demyelinating disorders. Many demyelinating disorders have previously been resistant to therapy. Furthermore, until recently, the treatment of human demyelinating disorders has relied exclusively on the use of immunosupressive agents such as corticosteroids and cyclophosphamide, which although providing limited benefit to patients, can be associated with potentially serious side effects. The introduction of interferon preparations has provided efficacy in the treatment of certain demyelinating disorders (e.g. multiple sclerosis). However, as benefits are apparent in only a portion of the subgroup of patients classified as suitable for tratment, then management of the disease is still insufficient with such preparations.
[0008] The present inventors have now provided evidence in support of the involvement of glutamate in the pathogenesis of demyelinating disorders. They have established a link between neuronal demyelination and glutamate-mediated cell death using accepted animal models of a demyelinating disorder.
[0009] The present invention represents a major advance over prior art methods in the treatment of demyelinating disorders.
[0010] According to one aspect of the present invention, there is provided the use of an inhibitor of the interaction of glutamate with the AMPA and/or kainate receptor complex in the manufacture of a medicament for treating a demyelinating disorder.
[0011] The term “inhibitor of the interaction of glutamate with the AMPA and/or kainate receptor complex” is used herein to include moieties that bind to the AMPA and/or kainate receptor or to glutamate so as to prevent or reduce the binding of glutamate to its binding site on the AMPA and/or kainate receptor. Such moieties may bind in a competitive or non-competitive manner. They are referred to herein as “antagonists” of the binding of glutamate to the AMPA and/or kainate receptor. A skilled person is able to identify substances that may be useful as antagonists of the present invention by binding studies. For example, the AMPA and/or kainate receptor, a part thereof including said glutamate binding site, or a glutamate molecule can be used to screen for substances that bind thereto, preferably in a highly specific manner. Such binding studies can be part of a screening program for identifying or designing potential therapeutic agents. More specifically, a skilled person could identify inhibitors of the interaction of glutamate with the AMPA and/or kainate receptor complex using, for example, in vitro calcium ion-increase assays or the whole cell configuration of the patch clamp technique. Cells expressing the AMPA receptor complex could be obtained, for example, from dissociated cortical or hippocampal cells. Cells expressing the kainate receptor complex could be obtained, for example, from dissociated dorsal root ganglion cells. Inhibition of the interaction of agonists, for example glutamate, AMPA or kainate, of the AMPA and/or kainate, receptor complex could be assayed by incubation of the agonist with and without antagonist and the cellular response (eg change in intra-cellular calcium ion concentration or change in membrane potential) measured.
[0012] The term “inhibitor of the interaction of glutamate with the AMPA and/or kainate receptor complex” also includes moieties that prevent a signal being transmitted that would otherwise occur when glutamate binds to the AMPA and/or kainate receptor. Preferred such moieties are AMPA and/or kainate receptor channel blockers. The term “AMPA and/or kainate receptor channel blocker” is used herein to refer to moieties that reduce the permeability of ion channels associated with the AMPA and/or kainate receptor in vivo (preferably to Na+ K+ and/or Ca2+ ions).
[0013] Various antagonists and AMPA receptor channel blockers that are within the scope of the present invention will now be described in greater detail:
[0014] Antagonists
[0015] The antagonists of the present invention include L-glutamate derivatives such as e.g. L-glutamic acid diethylester, &agr;-amino-3-hydroxy-5-methyl-4-isoxazolepropionate derivatives such e.g., &agr;-amino-3-hydroxy-5-tert-buthyl-4-isoxazolepropionic acid, quinoline, quinoxaline, quinoxalinedione, quinazolinone, phenylpyridazino-indole-1,4-dione, indeno-pyrazinone, indeno-pyrazine-carboxylic acid, indolo-pyrazinone, imidazo-pyrazinone, amino-phenyl-acetic acid, benzothiadiazine, 4-hydroxypyrrolone, 4-hydroxy-pyrrolo-pyridazinone, quinolone, amino alkanoic acid, isatin, nitroquinolone, phenyl-azolophthalazine, amino- or desamino-2,3-benzodiazepine, 2,3-benzodiazepin-4-one, &bgr;-carboline-3-carboxylic acid, alkoxy-phenyl-benzodiazepine, acetyl-aminophenyl-dihydro-methyl-dioxolo-benzodiazepine, oxadiazol, isatinoxime, decahydroisoquinoline, and sulphamate.
[0016] Further substances that may be useful as antagonists are listed below:
List of Antagonists[0017] (1) &ohgr;-[2-(Phosphonoalkyl)phenyl]-2-aminoalkanoic acids (I) in WO 93-05772 as shown below: 1
[0018] &ohgr;-[2(Phosphonoalkyl)phenyl]-2-aminoalkanoic acids represented by formula (I), wherein n and m independently are 0, 1, 2 or 3; R1 is selected from the group consisting of hydrogen and R2; R2 is selected from the group consisting of hydrogen, halogen, halomethyl, nitro, amino, alkoxy, hydroxyl, hydroxymethyl, C1 to C6 lower alkyl, C7 to C12 higher alkyl, aryl and aralkyl, wherein if R2 is hydrogen, R1 is not hydrogen; R3 is selected from the group consisting of hydrogen and C, to C6 lower alkyl; the stereoisomers thereof in their resolved or racemic form, and pharmaceutically acceptable salts thereof
[0019] (2) Fused pyperazine derivatives in WO 92-07847 as shown below: 2
[0020] A pyperazine derivative represented by general formula (Ia) wherein Z represents C or N, provided that two Zs are not N atoms at the same time; R1 represents (1a) wherein X represents N or R8C, R6 represents H or alkyl, and R7 and R8 represent each H, alkyl, nitro or phenyl, or alternatively R7 and R8 are combined together to represent butadienylene or 1,4-butylene; R2 and R3 represent each H, F, cyano, acyl, nitro, alkyl, morpholino or R1; R4 and R5 represent each H, hydroxy, alkyl, cycloalkyl, heterocycle, phenyl or Y-substituted alkyl; Y represents hydroxy, acyloxy, F-substituted methyl, cycloalkyl, tetrahydrofuryl, carboxyl, alkoxy carbonyl or NR9R10; and R9 and R10 represent H or alkyl, or alternatively R9 and R10 are combined together to represent a 5- or 6-membered cyclic group which may contain oxygen atom(s).
[0021] (3) Triazoloquinoxalin-1,4-diones (I) and (II) in WO 93-06103 an shown below: 3
[0022] Quinoxaline compounds represented by formula (I) or (II), wherein R1 and R2 are independently hydrogen, C1-6-alkyl, halogen, NO2, NH2, CN, CF3, SO2NR4R5 wherein R4 and R5 are independently hydrogen or C1-6-alkyl, or COR6 wherein R6 is C1-6-alkyl; and R3 is hydrogen, C1-6-alkyl or CF3, and compositions thereof.
[0023] (4) [1,2,4]Triazolo[4,3-a]quinoxalinone derivatives (I) in WO 96-08493 A1 as shown below: 4
[0024] [1,2,4]triazolo[4,3-a]quinoxalinone compounds of general formula (I) wherein R1 is POX′X″ or alkyl substituted with COX′ or POX′X″, and X′ and X″ independently are hydroxy or alkoxy, and R6, R7, R8 and R9 independently are hydrogen; alkyl; halogen; NH2; NO2; CN; CF3 SO2NY′Y″ OR COZ′ wherein Z′ is NY′Y″ or alkyl and Y′ and Y″ independently are hydrogen or alkyl; triazolyl; imidazolyl substituted with phenyl or alkyl.
[0025] (5) [1,2,4]Triazolo[4,3-a]quinoxalinone derivatives (I) in WO 96-08492 A1 as shown below: 5
[0026] [1,2,4]triazolo[4,3-a]quinoxalinone compounds of general formula (I) wherein R1 is POX′X″ or alkyl substituted with COX″ or POX′X″ and X′ and X″ independently are hydroxy or alkoxy, and R6, R7, R8 and R9 independently are hydrogen; alkyl; halogen; NH2, NO2, CN, CF3, SO2NY′—Y″, COZ′ wherein Z′ is NY′Y″ or alkyl and Y′ and Y″ independently are hydrogen or alkyl; triazolyl; imidazolyl, piperidino, piperazinyl, morpholino or thiomorpholino; all rings optionally being substituted.
[0027] (6) Pyrrolylquinoxalindiones (I) in WO 97 49701 as shown below: 6
[0028] Pyrrolylquinoxalindiones of formula (I) and their tautomeric and isomeric forms and their physiologically acceptable salts, in which R1 is hydrogen, C1-C6 alkyl, substituted by hydroxyl or carboxyl, R2 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, a chlorine, fluorine or bromine atom, a trihalogen methyl, cyano, or nitro group or SO2C1C4 alkyl, R3 is COOH or a radical hydrolysable to form the carboxyl group, and n is 1 or 2.
[0029] (7) Imidazole-substituted quinoxalinedione derivatives (I) in WO 9746555 as shown below: 7
[0030] Substituted imidazole quinoxalinedione derivatives represented by general formula (1), wherein each symbol has the following meaning: A: (CH?2?)m or Ph—(CH2)p (Ph being phenyl); X: oxygen or NR4; R1: hydrogen, hydroxy or triazolyl, provided that X may be a bond when R1 is triazolyl; R2: hydrogen, nitro, halogenated lower alkyl, cyano, amino, mono- or di (lower alkyl)amino, or halogeno; R3 and R4; the same or different and each representing hydrogen or lower alkyl; n: 0, 1 or 2; m: an integer of 2 to 6; and p: an integer of 1 to 6.
[0031] (8) Heterocyclically substituted imidazoloquinoxalines (I) in WO 97-34896 as shown below: 8
[0032] Imidazoloquinoxalines of formula (1), wherein R1 to R4 have the meanings given in the description in the corresponding patent (WO 97-34896) and R5 is a five-member optionally substituted heterocycle with between 1 and 4 nitrogen atoms or with 1 or 2 nitrogen atoms and an oxygen or sulphur atom, or an R6-substituted phenyl ring.
[0033] (9) Quinoxaline derivatives (I) in WO 97-32858 as shown below: 9
[0034] Quinoxaline derivatives of the formula (I) wherein R1 is alkyl, halo (lower) alkyl, amino, aryl or heterocyclic group, R2 is hydrogen or lower alkyl, R3 and R4 are each independently hydrogen, cyano, nitro, halogen, lower alkyl, halo (lower) alkyl, lower alkoxy, halo (lower) alkoxy, di (lower)-alkylamino, aryl which may have one or more substituents(s), heterocyclic group which may have one or more substituents(s), lower alkylthio which may have one or more substituents (s), heterocyclicthio, lower alkylsulfonyl, lower alkylaminosulfonyl, or heterocyclicsulfonyl, a group of the formula: 10
[0035] A is the group of the formula: 11
[0036] It is to be noted the object compound (I) may include one or more stereoisomers due to asymmetric carbon atom (s) and double bond, and all of such isomers and a mixture thereof are included. It is further to be noted that isomerization or rearrangement of the object compound (I) may occur due to the effect of the light, acid, base or the like, and the compound obtained as the result of said isomerization or rearrangement is also included within the scope of the present invention. It is also to be noted that the solvating form of the compound (I) (e.g. hydrate, etc.) and any form of the crystal of the compound (I) are included within the scope of the present invention.
[0037] (10) Condensed 2,3-benzodiazepine derivatives (I) in WO 97-28163 as shown below: 12
[0038] 2,3-Benzodiazepine derivatives of the formula (I) wherein R1 and R2 are identical or different and hydrogen, C1-C6-alkyl, nitro, halogen, cyano, the group —NR8R9, —O—C1-4-alkyl, —CF3, OH or C1-6-alkanoyloxy; R3 and R4 are identical or different and hydrogen, halogen, C1-C6-alkoxy, hydroxy, thiocyanate, C1-C6-alkylthio, cyano, COOR12, PO3R13R14, C1-C6-alkanoyl, C1-C6-alkanoyloxy, eventually with C1-C4-alkoxy or phenyl-substituted C2-6-alkynyl, eventually with C1-4-alkoxy or phenyl-substituted C2-6-alkenyl, eventually with halogen, hydroxy, C1-C6-alkoxy, C1-C6-thioalkyl, NR10—R11-substituted C1-C6-alkyl, C3-7-cycloalkyl or eventually a substituted aryl- or hetaryl-rest; R8 and R9 are identical or different and hydrogen, C1-C6-alkyl or the group-CO-C1-6-alkyl; R10 and R11 are identical or different and hydrogen, C1-C6-alkyl or C1-6-alkanoyl or together with the nitrogen atom will bild a 5-7 branched saturated heterocyclus, which will contain and can be susbtituted with a further oxygen-, sulfur or nitrogen atom; R12, R13, R14 are identical or differnt and H or C1-C6-alkyl; X hydrogen or halogen; Y C1-6-alkoxy or X and Y together —O—(CH2)n-O—; n means 1, 2 or 3 and A together with the nitrogen will form a saturated or an unsaturated 5 armed heterocyclus, which can contain 1-3 nitrogen atoms and/or a oxygen atom and/or one or two carbonyl groups or their isomers or physiological salts thereof.
[0039] (11) 1,2,3,4-Tetrahydroquinoxalindione derivatives (I) in WO 96-10023 as shown below: 13
[0040] A 1,2,3,4-tetrahydroquinoxalindione derivative represented by general formula (I) or a salt thereof, an NMDA-glycine receptor and/or AMPA receptor antagonist and a kainate neurocytotoxicity inhibitor each containing the same, and a medicinal composition comprising the above-mentioned compound and pharmaceutically acceptable carriers: wherein X represents N or CH; R represents imidazolyl or di(lower alkyl)amino; R1 represents (I) halogeno, nitro, cyano, carboxy, amino, mono- or di(lower alkyl) amino, lower alkanoyl, lower alkythio, lower alkylsulfinyl, lower alkylsulfonyl, or carbamoyl, (2) lower alkyl or lower alkoxy which may be substituted by halogeno, carboxy or aryl, or (3) phenyloxy which may be substituted by lower alkoxycarbonyl or carboxy; R2 represents hydroxy, lower alkoxy, amino, or mono- or di(lower alkyl)amino; and A represents optionally substituted alkylene or —O—B— (B being lower alkylene); provided the case wherein R represents imidazolyl, R1 represents cyano, A represents ethylene and R2 represents hydroxy is excepted.
[0041] (12) New heterocyclic substituted imidazoloquinoxalinones (I) in WO 96-10572 as shown below: 14
[0042] Imidazoloquinoxalinones of the formula (I), in which R1 stands for hydrogen, branched or linear C1-5-alkyl or a phenyl, pyridyl or thienyl group possibly substituted by one to two chlorine atoms, a trifluoromethyl, a nitrodioxy or a methylene dioxy group; R2 stands for hydrogen, C1-5-alkyl or C3-8-dialkylaminoalkyl; R3 stands for a chlorine or bromine atom, a trifluoromethyl, cyano or nitro group; A stands for a five-membered heterocycle with 1-4 nitrogen atoms or 1-2 nitrogen atoms and one oxygen or sulphur atom possible substituted by R4 and R5; the radicals R4 and R5, that may be the same or different, stand for hydrogen, C1-5-alkyl, C1-5-hydroxyethyl, phenyl, phenyl substituted by a chlorine atom, a trifluoromethyl or nitro group, —CHO, —COOH, —COO—C1-5-alkyl, —CH2—NR6R7 (in which R6═H, C1-5-alkyl, R7═H, C1-5-alkyl), —CH2—NH—CO—R8 (in which R8═C1-5-alkyl, phenyl, a phenyl group or an heteroaryl group possibly substituted by a chlorine atom of a nitro or trifluoromethyl group) or —CH2—NHCONHR8, and B stands for a bond or a C1-5-alkylene chain. Also disclosed are the tautomer and isomer forms of these compounds, as well as their physiologically compatible salts.
[0043] (13) Fused indole and quinoxaline derivatives (I) in WO 9608495 A1 as shown below: 15
[0044] Compounds having formula (O) or a pharmaceutically acceptable salt thereof wherein: R1 is hydrogen, alkyl or benzyl; X is O or NOR2, wherein R2 is hydrogen, alkyl or benzyl; Y is N—R4 wherein R4 is hydrogen, OH or alkyl; n is 0 or 1; R6 is phenyl which is substituted one or more times with substituents selected from the group consisting of SO2NR′R″, CONR′R″, and COR′″ wherein R′ and R″ each independently are hydrogen, alkyl, or —(CH2)p—W, wherein p is 0, 1, 2, 3, 4, 5, or 6, and W is hydroxy, amino, alkoxycarbonyl, or phenyl which may be substituted one or more times with substituents selected from the group consisting or halogen, CF3, NO2, ammo, alkyl, alkoxy or methylenedioxy; or wherein R′ and R″ together are (CH2),Z(CH2), wherein r and s each independently are 0, 1, 2, 3, 4, 5 or 6 and Z is O, S, CH2 or NR″″ wherein R′″ is hydrogen, alkyl, or —(CH2)p—W, wherein p is 0, 1, 2, 3, 4, 5 or 6, and W is hydroxy, amino, alkoxycarbonyl, or phenyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF3, NO2, amino, alkyl, alkoxy or methylenedioxy; and wherein R′″ is hydrogen, alkyl, alkoxy or phenyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF3, NO2, ammo, alkyl, alkoxy or methylenedioxy; A is a ring of five to seven atoms fused with the benzo ring at the positions marked a and b.
[0045] (14) [1,2,4]Triazolo[4,3-a]quinoxaline compounds (I) in WO 94-26746 as shown in below: 16
[0046] [1,2,4]Triazolo[4,3-a]quinoxaline derivatives of general formula (I) wherein one of R1 and R2 is a 5- or 6-membered N-containing heterocyclic ring optionally substituted, or a fused ring system comprising a 5- or 6-membered N-containing heterocyclic ring optionally substituted; and the other of R1 and R2 is H, alkyl, alkoxy, halogen, NO2, NH2, CN, CF3, COC1-6-alkyl or SO2NR′R″, wherein R′ and R″ are independently H or alkyl and X is O or S; and pharmaceutically acceptable salts thereof.
[0047] (15) [1,2,4]Triazolo[4,3-a]quinoxaline derivatives (I) in WO 94-21639 as shown below: 17
[0048] Quinoxaline compounds of general formula (1) wherein R1 is COX′, POX′X″ or alkyl substituted with COX″ OR POX′X∴, and X′ and X″ independently are hydroxy or alkoxy, and R6, R7, R8 and R9 independently are hydrogen, alkyl, halogen, NH2, NO2, CN, CF3, SO2NY′Y″ or COZ′ wherein Z′ is NY′Y″ or alkyl and Y′ and Y″ independently are hydrogen or alkyl, triazolyl, imidazolyl, imidazolyl substituted with phenyl or alkyl, or R6 and R7, or R8 and R9, together form a further fused ring.
[0049] (16) 2H-1,2,4-Benzothiadiazine-1,1-dioxide-3-carboxylic acid derivatives (I) WO 93-21171 as shown below: 18
[0050] The present invention relates to the use of derivatives of the 2H-1,2,4-benzothiadiazin-1,1-dioxide-3-carboxylic acid of the above formula or the salts of such compound or of intermediates of such compound for the preparation of AMPA receptor antagonists and to new componds of the formula (I), their preparation and the medications in which they are found.
[0051] In the formula (I): R1 is carboxy, alkoxycarbonyl, tetrazolyl, —CO—NH2, —CO—NH-alk, —CO—N(alk)2, —CO—NHOH, —CO—N(alk)OH, —CO—NH—O—R5, —CO—N(alk)-OR5 or a group that may be converted into a carboxyl moiety in vivo; R2, R3 and R4 are the same or different and are selected from the group consisting of hydrogen, halogen or alkyl; R5 is alkyl or phenylalkyl.
[0052] The term alk refers to an alkyl or alkylene group. Clearly, the compounds of the present invention include the tautomers of the compounds of the formula (a). The groups, convertible into carboxyl moieties in vivo, include —CO—R6, in which R6 is O-alk-R7, —O-alk-O—CO-alk, —O-alk-O—COOalk, —O-alk-O—CO—R7, —O-alk-OH, —O-alk-O-alk, —O-alk-S-alk, —O-alk-O—R7, —O-alk-S—R7, —O-alk-COOH, —O-alk-COOalk, —O-alk-NR8R9, —NH-alk-O—CO-alk, —NH-alk-O—COOalk, —NH-alk-O—CO—R7, —NH-alk-OH, —NH-alk-O-alk, —NH-alk-S-alk, —NH-alk-O—R7, —NH-alk-S—R7, —NH-alk-COOH, —NH-alk-COOalk, —NH-alk-NR8R9. In these definitions, R is alkyl or alkylene, R7 phenyl, R8 and R9 are the same or different and are selected from the group consisting of hydrogen, alkyl, phenyl or phenylalkyl or form with the oxygen atom they are attached to a piperidinyl, morpholinyl or pyrrolidinyl ring. The halogen atoms are selected from the following: fluoride, chloride, bromide or iodide. Unless otherwise stated, in the above and below definitions, the alkyl, alkoxy and alkylene groups are a straight or branched alkyl chain having one to six carbon atom, and preferably one to four carbon atoms. The compounds of the formula (I) in which either R2, R3 and R4 are hydrogen and R1 is carboxy, alkoxycarbonyl, —CO—NH2 or —CO—NH-alk, or R4 a chloride or bromide atom, R2 and R3 are hydrogen and R1 is carboxy, alkoxycarbonyl —CO—NH2 or —CO—NH-alk, or R3 a chloride or bromide atom, R2 and R4 are hydrogen and R1 is carboxy, alkoxycarbonyl, —CO—NH2 or —CO—NH-alk. The present invention include also other compounds of the formula (I), their salts or intermediates of their salts. In these compounds, R1 is carboxy, alokoxycarbonyl, tetrazolyl, —CO—NH2, —CO—NH-alk, —CO—N(alk)2, —CO—NHOH, —CO—N(alk)OH, CO—NH—O—R5, CO—N(alk)-OR5 or —CO—R6, in which R6 is —O-alk-R7, —O-alk-O—CO-alk, —O-alk-O—COOalk, —O-alk-O—CO—R7, —O-alk-OH, —O-alk-O-alk, —O-alk-S-alk, —O-alk-O—R7, —O-alk-S—R7, —O-alk-COOH, —O-alk-COOalk, —O-alk-NR8R9, —NH-alk-O—CO-alk, —NH-alk-O—COOalk, —NH-alk-O—CO—R7, —NH-alk-OH, —NH-alk-O-alk, —NH-alk-S-alk, —NH-alk-O—R7, —NH-alk-S—R7, —NH-alk-COOH, —NH-alk-COOalk, —NH-alk-NR8R9, R2, R3 and R4 are the same or different and are selected from the group consisting of hydrogen, halogen or alkyl, R5 is alkyl or phenylalkyl, R7 is phenylalkyl, R and R9 are the same or different and are selected from the group consisting of hydrogen, alkyl, phenyl or phenylalkyl or form with the oxygen atom they are attached to a piperidinyl, morpholinyl or pyrrolidinyl ring. The term alk refers to an alkyl or alkylene group. The present invention does not include the compounds of the formula (I) in which either R2, R3 and R4 are hydrogen and R1 is carboxy, alkoxycarbonyl, —CO—NH2 or —CO—NH-alk, or R4 a chloride or bromide atom, R2 and R3 are hydrogen and R1 is carboxy, alkoxycarbonyl —CO—NH2 or —CO—NH-alk, or R3 a chloride or bromide atom, R2 and R4 are hydrogen and R1 is carboxy, alkoxycarbonyl, —CO—NH2 or —CO—NH-alk.
[0053] (17) Fused quinoxalinone derivatives (I) in WO 93-20077 as shown in below: 19
[0054] A fused quinoxalinone derivative represented by general formula (I), a tautomeric isomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which has a glutamate receptor antagonism and is useful as anti-ischemic and pshychotropic, wherein a represents a 5-membered heterocyclic group containing two or three nitrogen atoms, R1 represents nitro or trifluoromethyl, X represents (a), (b), (c) or (d), and R2, R3, R4, R5 and R6 may be the same or different from one another and each represents hydrogen or lower alkyl which may be substituted by mono- or di(lower alkyl)amino.
[0055] (18) Quinolone derivatives (1) in WO 93-11115 as shown in below: 20
[0056] Compounds of formula I or a pharmaceutically acceptable salt thereof or a prodrug thereof: wherein R represents a hydrogen atom, an amino group, a carboxy or C2-6 alkoxycarbonyl group, or a group of formula -A-B-E, in which A represents a chemical bond, an oxygen or sulphur atom, or an —NH— group; B represents a carbonyl (C═O) or sulphonyl (SO2) group, or a straight or branched alkylene chain containing from 1 to 6 carbon atoms; and E represents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cyano, phenyl, tetrazolyl, methyloxadiazolyl, —NRaRb, —CORa, —C(═N.ORa)Rb, —CO2Ra, —CONRaRb, —CONRa.ORb or —CH2CO2R8; R1 and R2 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, —ORa, —SRa, —SORa, —SO2Ra, —SO2NRaRb, —NRaRb, NRaCORb, —NRaCO2Rb, —CORa, —CO2Ra or —CONRaRb; or R1 and R2 together represent the residue of a carbocyclic or heterocyclic ring; one of R3, R4, R5 and R6 represents hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, —ORa, —SRa, —SORa, —SO2R2, —SO2NRaRb, —NRaRb, —NRaCORb, —NRaCO2Rb, —CORa, —CO2Ra or —CONRa or —CONRaRb, and the other three of R3, R4, R5 and R6 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, —ORa, —SRa, —SORa, —SO2Ra, —SO2NRaRb, —NRaRb, —NRaCORb, —NRaCO2Rb, —CORa, —CO2Ra or —CONRaRb, and Ra and Rb independently represent hydrogen, hydrocarbon or a heterocyclic group.
[0057] (19) Quinolone derivatives (I) in WO 93-10783 as shown below: 21
[0058] Compounds of formula I or a pharmaceutically acceptable salt thereof or a prodrug thereof wherein R represents a hydrogen atom, an amino group, a carboxy or C2-6 alkoxycarbonyl group, or a group of formula -&agr;-&bgr;-&egr;, in which a represents a chemical bond, an oxygen or sulphur atom, or an —NH— group; &bgr; represents a carbonyl (C═O) or sulphonyl (SO2) group, or a straight or branched alkylene chain containing from 1 to 6 carbon atoms; and &egr; represents C1-6 alkyl, C2-6 alkenyl, phenyl, —NRaRb, —CO2Ra or —CH2CO2Ra; R1 is a group of part formula (i) or (ii):
—(CH═CH)n-T (i) 22
[0059] wherein U and V independently represent cyano, carboxy, —COR6, —CO2R6, —CO.SR6, —CONHOH or —CONHNH2; n is zero or 1, preferably zero; T represents cyano, carboxy, —COR6, —CO2R6, —CO.SR6, —CONHOH, —CONHNH2 or a group of formula in which the broken circle represents two non-adjacent double bonds in any position in the five-membered ring; B represents a bond or a carbonyl group (C═O); W, X, Y and Z independently represent oxygen, sulphur, nitrogen or carbon, provided that no more than one of W, X, Y and Z represents oxygen or sulphur and at least one of W, X, Y and Z is other than carbon; one of E, F and G represents nitrogen or carbon and the remainder represent carbon; A1, A2 and A3 represent one, two or three substituents not exceeding the maximum number permissible by the disposition of heteroatoms in the five- or six-membered ring, which substituents are independently selected from hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, —ORa, —SR2, —SORa, —SO2Ra, —SO2NRaRb, —NRaRb, —NRaCORb, —NRaCO2Rb, —CORa, —CO2Ra or —CONRaRb; or A1 and A2 or A2 and A3 together represent the residue of an aromatic or heteroaromatic ring; 23
[0060] one of R2, R3, R4 and R5 represents hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, —ORa, —SRa, —SORa, —SO2Ra, —SO2NRaRb, —NRaRb, —NRaCORb, —NRaCO2Rb, —CORa, —CO2Ra or —CONRaRb, and the other three of R2, R3, R4 and R5 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, —ORa, —SRa, —SORa, —SO2Ra, —SO2NRaRb, —NRaRb, —NRaCORb, —NRaCO2Rb, —CORa, —CO2Ra or —CONRaRb; or R2 and R3, R3 and R4 or R4 and R5 together represent the residue of an aromatic or heteroaromatic ring; R6 represents hydrocarbon or a heterocyclic group; and Ra and Rb independently represent hydrogen, hydrocarbon or a heterocyclic group.
[0061] (20) Quinoxaline derivatives (I) in WO 93-08173 as shown below: 24
[0062] Quinoxaline derivates of the formula (I), in which R1 is C1-12-alkyl substituted by R2, C2-12-alkenyl substituted by R2, C2-12-alkinyl substituted by R2, C3-7-cycloalkyl substituted by R2, —(CH2)n—C6-12-aryl substituted by R2 in the aryl or alkyl residue or —(CH2)n-hetaryl substituted by R2 in the hetaryl or alkyl residue; R4 is hydrogen, C1-12-alkyl substituted by R2, C2-12-alkenyl substituted by R2, C2-12-alkinyl substituted by R2, (CH2)n—C6-12-aryl substituted by R2 in the aryl or alkyl residue, or —(CH2)n-hetaryl substituted by R2 in the hetaryl or alkyl residue; R5, R6, R7 and R8 are the same or different and represent hydrogen, halogen, nitro, NR9R10, NHCOR11, SO2R12, C3-7-cycloalkyloxy, COR13, cyano, CF3, C1-6-alkyl, C1-4-alkoxy or imidazole possibly substituted by cyano, C1-4-alkyl or —COO—C1-6-alkyl or R5 and R6 or R7 and R8 represent a condensated benzene ring, and R2 stands for —CO—R3, or —PO—XY and is present once or twice in the same or a different form.
[0063] (21) Substituted 2,3-benzodiazepin-4-one (I) in WO 97-34878 as shown below: 25
[0064] Substituted 2,3-benzodiazepin-4-one represented by formula (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein: R1 and R2 are independently hydrogen, alkyl, haloalkyl, aryl, fused aryl, a carbocyclic group, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl or thioalkyl; or R1 and R2 are taken together to form a carbocycle or heterocycle; R3 is hydrogen, alkyl, haloalkyl, aryl, fused aryl, a carbocyclic group, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, COR, CO2R and CONRxRy, wherein R, Rx and Ry are independently hydrogen, alkyl, haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, or aminoalkyl; or Rx and Ry are taken together to form a carbocycle or heterocycle; R4 is substituted or unsubstituted aryl, fused aryl, a carbocyclic group, a heterocyclic group, or a heteroaryl group; R5 and R6 are independently hydrogen, halo, haloalkyl, aryl, fused aryl, a carbocyclic group, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, carboxy, carbonylamido or alkylthiol; R7 and R8 are independently hydrogen, halo, haloalkyl, aryl, fused aryl, a carbocyclic group, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido or alkylthiol; or R7 and R8 are taken together to form a carbocycle or heterocycle, for example, —OCH2O, —(CH2)3—, —(CH2)4, —OCH2CH2O—, —CH2N(R)CH2—, —CH2CH2N(R)CH2—, —CH2N(R)CH2CH2—, —N(Me)—C(O)—O— and —N═C—C═N—, wherein R is a defined above; and n is 0 or 1.
[0065] (22) 2,3-Disubstituted-4(3H)-quinazolinone in WO9743276 as shown below: 26
[0066] Bicyclic compounds of the formula wherein R1 is optionally substituted phenyl of the formula Ph1 or heteroaryl wherein said heteroaryl is selected from the group consisting of pyridin-2-yl, pyridin-3-yl and pyridin-4-yl, wherein said heteroaxyl may optionally be substituted on any of the ring carbon atoms capable of forming an additional bond, up to a maximum of three substituents per ring, with a substituent selected from hydrogen, (C1-C6)alkyl, halogen, trifluoromethyl, amino-(CH2)n—, (C1-C6)alkylamino-(CH2)n—, di(C1-C6)alkyl-amino-(CH2)—, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkyl-O—(C1-C6)alkyl-, —CN, (C1-C6)alkyl-C—O—, (C, —C6)alkyl-, (C1-C6)alkyl-O—C—O—(C1-C6)alkyl, (C1-C6)alkyl-C—O—, hydroxy, H—C(═O)—, (C1-C6)alkyl-C(═O)—(CH2)n—, HO—C(═O)—(CH2)n—, (C1-C6)alkyl-O—C(═O)—(CH2)n—, NH2—C(═O)—(CH2)n—, (C1-C6)allyl-NH—C(═O)—(CH2)n—, and di(C1-C6)aqlyl-NH—C(O)(CH2)n, wherein said Ph1 is a group of the formula 27
[0067] R2 is phenyl of the formula Ph2 or a five or six membered heterocycle, wherein said 6-membered heterocycle has the formula 28
[0068] wherein “N” is nitrogen; wherein said ring positions “K”, “L” and “M” may be independently selected from carbon or nitrogen, with the proviso that i) only one of “K, “L” or “M” can be nitrogen and ii) when “K”, “L” or “M” is nitrogen then its respective R15, R16 or R17 is absent; wherein said five membered heterocycle has the formula 29
[0069] wherein said “T” is —CH—, N, NH, O or S; wherein said ring positions “P” and “Q” may be independently selected from carbon, nitrogen, oxygen or sulfur; with the proviso that only one of “P”, “Q” or “T” can be oxygen or sulfur and at least one of “P”, “Q” or “T” must be a heteroatom; wherein said Ph2 is a group of the formula 30
[0070] R3 is hydrogen, halo, —CN, —NO2, CF3, (C1-C6)alkyl or (C1-C6)alkoxy; R5 is hydrogen, (C1-C6)alkyl, halo, CF3, (C1-C6)alkoxy or (C1-C6)alkylthiol; R6 is hydrogen or halo; R7 is hydrogen or halo; R8 is hydrogen or halo; R9 is hydrogen, halo, CF3, (C1-C6)alkyl optionally substituted with one to three halogen atoms, (C1-C6)alkoxy optionally substituted with one to three halogen atoms, (C1-C6)alkylthiol, amino-CH2)s—, (C1-C6)alkyl-NH—(CH2)s—, di(C1-C6)alkyl-N—(CH2)s—, (C3-C7)cycloalkyl-NH—(CH2)s—, H2N—(C═O)—(CH2)s—, (C1-C6)alkyl-HN—(C═O)(CH2)s—, di(C1-C6)alkyl-N—(C═O)—(CH2)s—, (C3-C7)cycloalkyl-NH—(CH2)s—, R13 O—(CH2)s—, R13 O—(C═O)(CH2)s, H(O═C)—NH—(CH2)s—, (C1-C6)alkyl-(O═C)-n-(CH2)s—, H(O═C)—(CH2)s-, (C1-C6)alkyl-(C═O)—, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkyl-, (C1-C6)alkyl-O—(C1-C6)alkyl-, and —CN; R10 and R14 are selected, independently, from hydrogen, halo, CF3, (C1-C6)alkyl optionally substituted with one to three halogen atoms, (C1-C6)alkoxy optionally substituted with one to three halogen atoms, (C1-C6)alkylthiol, amino-(CH2)p—, (C1-C6)alkyl-NH—(CH2)p—, di(C1-C6)alkyl-N—(CH2)p—, amino-(C1-C6)alkyl-NH—(CH2)p—, (C1-C6)alkyl-NH—(C1-C6)alkyl-NH—(CH2)p—, di(C1-C6)alkyl-N-(C1-C6)alkyl-NH—(CH2)p—, di(C1-C6)alkyl-N-(C1-C6)alkyl-N—(CH2)p—, H2C═O)—(CH2)p—, H2C═O)—(CH2)p—, (C1-C6)alkyl-HN—(C═O)—CH2)p—, (C3-C7)cycloalkyl-NY—(C═O)—(CH2)p—, R13O—(C═O)—(CH2)p—, H(O═C)O—, H(O═C)—O—(C1-C6)alkyl-, H(O═C)—NH—(CH2)p—, (C1-C6)alkyl-(O═C)—NH—(CH2)p—, —CHO, H—C(C═O)—(CH2)p—, (C1-C6)alkyl-(C—)—(CH2)p—, (C1-C6)alkyl-(O═C)—N—(CH2)p—, H(O═C)—N—(CH2)—, HO—(C1-C6)alkyl-N—(CH2)p—, (C1-C6)alkyl-(C═O)—O—NH—(CH2)p—, amino-(C1-C6)alkyl-O—(C═O)—O(CH2)p, (C1-C6)alkyl, (C1-C6)alkyl-NH—(C1-C6)alkyl-(C═O)—O—(CH2)p—, di(C1-C6)alkyl-N-(C1-C6)alkyl-(C═O)—O—(CH2)p—, amino-(C1-C6)alkyl-O—(C═O)—(CH2)p, (C1-C6)alkyl-NH—(C1-C6)alkyl-O—(C═O)—(CH2)p—, di(C1-C6)alkyl-N—(C1-C6)alkyl-O—(C═O)—(CH2)p—, hydroxy, hydroxy-(C1-C6)alkyl-, hydroxy-(C1-C6)allkyl-NH—(CH2)p—, (C1-C6)alkyl-O-(C1-C6)alkyl-, —CN, piperidine-(CH2)p—, pyrrolidine-(CH2)p—, and 3-pyrroline-(CH2)p—, wherein said piperidine, pyrrolidine and 3-pyrroline of said piperidine-(CH2)p—, pyrrolidine-(CH2)p— and 3-pyrroline-(CH2)p— moieties may optionally be substituted on any of the ring carbon atoms capable of supporting and additional bond, preferably zero to two substitutents, with a substituent independently selected from halo, CF3, (C1-C6)alkyl optionally substituted with one to three halogen atoms, (C1-C6)alkoxy optionally substituted with one to three halogen atoms, (C1-C6)alkylthiol, amino-(CH2)p—, (C1-C6)alkyl-NH—(CH2)p—, di(C1-C6)alkyl-N—(CH2)p—, (C3-C7)cycloalkyl-NH—(CH2)p—, amino-(C1-C6)alkyl-NH—(CH2)p—, (C1-C6)alkyl-NH—(C1-C6)alkyl-NH—(CH2)p—, di(C1-C6)alkyl-N-(C1-C6)alkyl-NH—(CH2)p—, (C1-C6)alkyl-O—(C1-C6)alkyl-, di(C1-C6)alkyl-N-(C1-C6)alkyl-N—(CH2)p—, H2N—(C═O)—(CH2)p—, (C1-C6)alkyl-HN—(C═O)—(CH2)p—, di(C1-C6)alkyl-N—(C═O)(CH2)p, C3-C7)cycloalkyl-NH—(C═O)_(CH2)p—,R13O—(CH2)p—, R13O—(C═O)—(CH2)p—, H(O═C)O—, H(O═C)—O(C1-C6)alkyl-, H(O═C)—NH—(CH2)p—, (C1-C6)alkyl-(O═C)—NH—(CH2)p—, —CHO, H—(C═O)—(CH2)p—, (C1-C6)alkyl-(C═O)—, (C1-C6)alkyl-(O═C)—N—(CH2)p—, H(O═C)-n-(CH2)p—, HO—(C1-C6)alkyl-N—(CH2)p—, (C1-C6)alkyl-(C═O)—O—NH—(CH2)p, amino-(C1-C6)alkyl-(C═O)—O—(CH2)p—, (C1-C6)alkyl-NH—(C1-C6)alkyl-(C═O)—O—(CH2)p—, di(C1-C6)alkyl-N-(C1-C6)alkyl-(C═O)—OCH2)p—, hydroxy, hydroxy-(C1-C6)alkyl-, hydroxy-(C1-C6)alkyl-NH—(CH2)p—, and —CN; R11 is hydrogen or halo; R12 is hydrogen, —CN or halo; R13 is hydrogen, (C1-C6)alkyl, (C1-C6)alkyl-(C═O)—, (C1-C6)alkyl-O—(C═O)—, (C1-C6)alkyl-NH—(C═O)—, or di(C1-C6)alkyl-N—(C═O)—; R15 is hydrogen, —CN, (C1-C6)alkyl halo, CF3, —CHO or (C1-C6)alkoxy; R16 is hydrogen, —CN, (C1-C6)alkyl, halo, CF3, —CHO or (C1-C6)alkoxy; R17 is hydrogen, —CN, (C1-C6)alkyl, amino-(C—C6)alkyl-, (C1-C6)alkyl-NH—(C1-C6)alkyl-, di(C1-C6)alkyl-N—(C1-C6)alkyl-, halo, CF3, —CHO or (C1-C6)alkoxy; n is an integer from zero to 3; each p is independently an integer from zero to 3; s is an integer from zero to 4; wherein the dashed bond represented an optional double bond; with the proviso that: i) when R9 is hydrogen, one of R11 and R12 is other than hydrogen; ii) when R1 is unsubstituted phenyl and R3 is hydrogen then (a) R2 can not be unsubstituted phenyl, thienyl or furyl or (b) R9 can not be CI or hydroxy when R10 and R11 are hydrogen, or (c) R10 or R11 can not be chloro when R9 and R12 are hydrogen; iii) when R3 is hydrogen; R6, R7 and R8 are hydrogen; and R5 is chloro or methyl, then (a) R2 can not be unsubstituted phenyl, thienyl or furyl or (b) R10 or R11 can not be chloro or (c) R9 or R12 can not be hydroxy, methyl or methoxy; iv) when R3 is hydrogen or chloro; R5 is methyl; R6, R7 and R8 are hydrogen; and K, L and M equal carbon, then (a) one of R14 through R17 must be other than hydrogen or (b) R17 must be other than hydrogen or methyl; v) when R1 is unsubstituted pyridin-2-yl and R3 is hydrogen, bromo or iodo then R2 can not be unsubstituted phenyl; vi) when R7 is chloro; R5, R6, and R8 are hydrogen; and R3 is hydrogen, then (a) R2 can not be unsubstituted phenyl, pyridyl, thienyl or furyl or (b) R9 or R12 can not be hydroxy when R10 and R11 are hydrogen; vii) when R2 is unsubstituted phenyl, R6, R7 and R8 are hydrogen, and R3 is hydrogen, then R5 can not be —CO2H; viii) when R2 is unsubstituted pyridin-2-yl, R5 and R7 are hydrogen, then R6 or R8 must be other than chloro; ix) when R2 is unsubstituted phenyl, R3 is hydrogen, and R5 and R7 are hydrogen, then one of R6 or R8 must be other than chloro; and the pharmaceutically acceptable salts of such compounds.
[0071] (23) Fused cycloalkyl quinoxalinedione (I) in WO 98-05651 as shown below: 31
[0072] Compounds represented by the formula (1) or pharmaceutically acceptable salts thereof wherein Z is a carbocyclic fused ring having 5 to 7 carbon atoms; X and Y are independently hydrogen, halogen, nitro, cyano, —CF3, —COOH, —CONR1R2, —COR3, —SO2R3, imidazolyl or imidazolidinyl, wherein R1 and R2 are independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl, aralkyl or join together to form a heterocyclic ring and wherein R3 is alkyl, haloalkyl, cycloalkyl, aryl or aralkyl; A is a bond, O, S, NR4, NR4CO, NR4CS, CONR4, CSNR4, CO or CS wherein R4 is hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl, aralkyl or when n=0 then R4 and B may join together to form a heterocyclic ring; B is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, R5, CN, COR5, PO3R52, SO2R5, or heterocyclic, wherein R5 is hydroxy, alkoxy, aralkoxy, aryloxy or NR1R2; and m and n are independently 0, 1, and 2, provided that (i) m is not 0 when A is O, CN, tetrazole or CO, except when A is CO and B is a heterocyclic or when A is 0 and B is COR5, PO3R52 or SO2R5; (ii) m is not 0 or 1 when A is NR4, except when B is COR5, PO3R52 or SO2R5; and (iii) n is not) when A is O, S, NR4, CONR4 and B is NR1R2, CN, COR5, or PO3R52.
[0073] (24) nimdazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylic acid derivatives (I) and their salts as shown in WO 96-02544 A1 as shown below: 32
[0074] Imidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylic acid derivatives having general formula (I) wherein R is N-alk, C(R4)R5, CH—R6 or C═R7, R1 and R2 are the same or different and are selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, amino, —N═CH—N(alk)alk′, nitro, cyano, phenyl, imidazolyl, SO3H, hydroxy, polyfluoralkoxy, carboxy, alkylcarbonyl, —NH—CO—NR11R12, —N(alk)-CO—NR11R12, —N(alk-Ar)-CO—NR11R12, —NH—CS—NR11R12, —N(alk)-CS—NR11R12, —NH—CO—NR11, —NH—CS—R24, —NH—C(═NR27)—NR10R12, —N(alk)-C(═NR27)—NR10R12, —CO—NR10R12, —NH—SO2—NR10R12, N(alk)-SO2—NR10R12, —NH—SO2—CF3, —NH—SO2-alk, —NR10R13, S(O)m-alk-Ar, —SO2—NR10R12 2-oxo-1-imidazolidinyl in which position 3 may be substituted by an alkyl group, or 2-oxo-1-perhydropyrimidinyl in which position 3 may be substituted by an alkyl group, R3 is carboxy, alkoxycarbonyl or carboxamide, R4 is alkyl, -alk-Het or phenylalkyl in which the phenyl group is substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR10, and -alk-COOR10, R5 is an alkyl group (the term C1-C11 alkyl represents a straight or branched alkyl chain having one to eleven carbon atoms), -alk-Het, NR8R9, —NH—CHO, —NH—COOR17, —NH—SO2R24, —COOR10, -alk-COOR10, -alk-CONR10R18, -alk-NR10R18, -alk-OH, -alk-CN, phenylalkyl in which the phenyl group is substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR10, and -alk-COOR10, —NH—CO—Ar in which Ar is substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR10, and -alk-COOR10, —NH—CO-Het, —NH—CO-alk-Het, —NH—CO-alk-COOR10, —NH—CO-alk-NR10R18, —NH—CO-alk-Ar in which Ar is substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR10, and -alk-COOR10, pyrrol-lyl possibly substituted by —COOR10, —NH—CO—NH-alk-Ar in which Ar is substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR10, and -alk-COOR10, —NH—CO—NH-Het, —NH—CO—NH-alk-Het, —NH—CO—NH—Ar in which Ar is substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR10, and -alk-COOR10, —NH—COalk, —NH—COcycloalkyl, —NH—CO—NH-alk or —NH—CO—NH2, or R4 and R5, together with the carbon atom they attached to, are a cycloalkyl group, R6 is hydrogen, hydroxy, alkyl (the term C1-C11 alkyl represents a straight or branched alkyl chain having one to eleven carbon atoms), -alk-OH, —NR14R15, -alk-NR14R15, alk-Het, —NH—CHO, —COOalk, -alk-COOR10, -alk-CO—NR10R21, phenylalkyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR10, and -alk-COOR10, —R16—COOR10, —CO—COOR10 or pyrrol-lyl which may be substituted by —COOR10, or 2-oxo-2,5-dihydropyrrol-1-yl, R7 is oxygen or NOH, NO-alk-COOR10, NO-alk, CHR19, NR10, C(COOR10)R20 or C(CONR10R21)R20, R8 is hydrogen, alkyl, -alk-COOR10, -alk-NR10R21, -alk-Het or phenylalkyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR10 and -alk-COOR10, R9 is hydrogen or alkyl, R10 is hydrogen or alkyl, R1, is hydrogen, alkyl (the term C1-C9 alkyl represents a straight or branched alkyl chain having one to nine carbon atoms), -alk-COOR10, alk-Het, -alk-NR12R10, phenylalkyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, carboxy, alkoxycarbonyl, cyano, and -alk-COOR10 or Het, phenyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, carboxy, alkoxycarbonyl, cyano, and -alk-COOR10 or Het, R12 is hydrogen or alkyl, R13 is alkyl, Het or alkoxycarbonyl, R14 and R15 are the same or different and are each an alkyl group or R14 is hydrogen and R15 is hydrogen, alkyl, —COR22, —CSR23 or SO2R24, R16 is a —CHOH or —CH(OH)-alk(C1-C5) chain, R17 is alkyl or phenylalkyl, R18 is hydrogen or alkyl, R19 is hydroxy, alkyl, alk-Het, —NR25R26, -alk-COOR10, -Het, phenyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, —COOR10, cyano, and -alk-COOR10, or, phenylalkyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, carboxy, alkoxycarbonyl, cyano, and -alk-COOR10, R20 is hydrogen or alkyl, R2, is hydrogen or alkyl, R22 is alkyl, cycloalkyl, —COOalk, -alk-COOR10, phenyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, —COOR10, cyano, and -alk-COOR10, phenylalkyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, —COOR10, cyano and -alk-COOR10,-alk-NR10R12, —NH—Ar in which Ar may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, —COOR10, cyano, and -alk-COOR10, -Het, -alk-Het, —OR17, —NH-alk-Ar in which Ar may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, carboxy, alkoxycarbonyl, —COOR10, cyano and -alk-COOR10, NH-alk-Het, —NH-alk, —NH2 or —NH-Het, R23 is —NH-alk, —NH—Ar, —NH-Het or —NH2, R24 is alkyl or phenyl, R25 and R26 are the same or different and are each alkyl or cycloalkyl, R27 is hydrogen or alkyl.
[0075] The term alk refers to an alkyl or alkylene group. The term alk′ refers to an alkyl group, m=0, 1 or 2. The term Ar refers to a phenyl group. The term Het refers to a heterocycle which is mono or poly saturated or unsaturated with four to nine carbon atoms and one or more heteroatom (O, S, N) which may be substituted with one or more of the following: alkyl, phenyl, or phenylalkyl.
[0076] Unless otherwise stated, in the above and below definitions, the alkyl or alkylene groups are a straight or branched alkyl chain having one to six carbon atom, the acyl groups have two to four carbon atoms, the cycloalkyl groups have three to six carbon atoms and the halogen are of the following: fluoride, chloride, bromide, or iodide.
[0077] Preferably, Het is one of the following rings: pyrrolyl, pyridyl, pyrimidinyl, imidazolinyl, thiazolyl, oxazolinyl, thiazolinyl, pyrazinyl, tetrazolyl, triazolyl. Each of these rings can possibly be substituted by one or more of the following: alkyl, phenyl or phenylalkyl. The preferred substitutants are methyl, phenyl or benzyl.
[0078] The compounds of the formula (I) in which R7 is NO-alk, C(COOR10)R20, C(CONR10R21)R20 or CHR19 can exist as isomers (E and Z). The compounds of the present invention include the isomers E and Z and their mixtures.
[0079] The compounds of the formula (I), in which R is CH—R6 and R6 is —CO—COOR10, can exist as tautomers (E and Z). The compounds of the present invention include the tautomers E and Z and their mixtures.
[0080] The compounds of the present invention include the eniantomers and diastereoisomers of the compounds of the formula (I), in which R is C(R4)R5 or CH—R6.
[0081] (25) Phthalazine derivatives (I) in DE 196 17 862 A1 as shown below: 33
[0082] Phthalazine derivatives of the formula I wherein R1 and R2 are identical or different and hydrogen, C1-C6-alkyl, nitro, halogen, the group —NR8R9, —O—C1-4alkyl or CF3; R3 and R4 are identical or different and hydrogen, an eventually substituted C1-C6-alkyl-, aryl- or hetaryl residue or C3-7-cycloalkyl; R8 and R9 are identical or different and hydrogen, C1-C6-alkyl or the group —CO—C1-6-alkyl, X hydrogen; Y C1-6-alkoxy or X and Y together —O—(CH2)n—O—; n 1, 2 or 3 mean and A forms together with nitrogen a fifemembered heterocycle, which can contain 1-3 nitrogen atoms, as wen as its isomers and pharmaceutically acceptable salts thereof.
[0083] Under alkyl one has to understand a linear or branched alkyl residue as for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sek. butyl, pentyl, isopentyl or hexyl, which can be substituted by C1-C6-alkoxy, halogen or C1-C6-alkonyl. If there is a halogenated alkyl residue present, then it can be multiple halogenated or perhalogenated such as CF3. Under halogen one has to understand fluoride, chloride, bromide and iodide. The aryl- and hetaryl residue R3 and R4 can be single or multiple substituted with halogen, C1-4-alkoxy or C1-4-alkyl. The alyl residue can contain 6-10 carbon atoms whereby phenyl is preferred. One might mention as a hetaryl residue for example pyridinyl. With cycloalkyl one means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, respectively, particularly C3-5-cycloalkyl. Suitable as alkanoyl residues are alphatic carbonic acid residues such as formyl, acetyl, propionyl, butanoyl,caproyl, valeroyl, trimethylacetyl and others. If A together with the nitrogen atom forms a 5-membered heterocycle, then is in position 4 an exocyclic double bond. Preferred are heteroaromatics with 1-3 nitrogen atoms, whereby for example A has the following meaning: 34
[0084] (26) 2,3-Benzodiazepine derivatives (I) in DE 196 04 920 A1 as shown below: 35
[0085] 2,3-Benzodiazepine derivatives having general formula (I) wherein X is hydrogen or halogen, Y—NR3— or —N═, R1 and R2 are identical or different and hydrogen, C1-C6-alkyl, nitro, halogen, the group —NR8R9, —O-C1-4-alkyl or —CF3, R3 is hydrogen, the group —CO—R10, C1-6-alkyl or C3-7cycloalkyl; R4 eventually substituted C1-C6-alkyl; R5 hydrogen or R4 and R5 together oxygen; R6 C1-4-alkyl; R8 and R9 are identical or different and hydrogen, C1-C6-alkyl or —CO—C1-6-alkyl; R10 hydrogen, eventually substituted C1-C6-alkyl, eventually substituted C6-10-aryl, the group —NR11R12, —O—C1-6 alkyl, C3-7-cycloalkyl, C26-alkenyl or —O—C3-7-cycloalkyl; R11 and R12 are identical or different and hydrogen, eventually substituted C1-C6-alkyl or eventually substituted C6-10-aryl and —C... C... a double bond or single bond means as well as their isomers and pharmaceutically acceptable salts thereof
[0086] (27) Dihydro-2,3-benzodiazepine derivatives (I) in WO 96-06606 as shown below: 36
[0087] Dihydro-2,3-benzodiazepine derivatives having general formula (I) wherein R is hydrogen or C1-C10 alkyl; X is an aromatic moiety selected from phenyl, thienyl, furyl, pyridyl, imidazolyl, benzimidazolyl, benzothiazolyl and phthalazinyl which is unsubstituted or substituted with one or more moieties chosen from the group consisting of halogen, hydroxy, cyano, nitro, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, carboxy, C1-C6 alkoxycarbonyl, acetyl, formyl, carboxymethyl, hydroxymethyl, amino, aminomethyl, methylenedioxy and trifluoromethyl; and “Aryl” represents p-nitrophenyl, p-aminophenyl or p-(protected amino) phenyl; or a pharmaceutically acceptable salt thereof
[0088] (28) 3-Substituted 3H-2,3-benzodiazepine derivatives (I) in WO 96-04283 A1 as shown below: 37
[0089] 3-Substituted 3H-2,3-benzodiazepine derivatives of general formula (I) wherein R1 and R2 are identical or different and hydrogen, C1-C6-alyl, nitro, halogen, the group —NR8R9, —O—C1-4-alkyl or CF3; R3 the group —C═O 38
[0090] R4 eventually substituted C1-C6-alkyl; R5 hydrogen or eventually substituted C1-C6-alkyl; R6 and R7 are identical or different and hydrogen, eventually substituted C1-C6-alkyl or eventually substituted aryl; R8 and R9 are identical or different and hydrogen, C1-C6-alkyl or the group 39
[0091] R10 hydrogen, eventually substituted C—C6-alkyl, eventually substituted aryl, the group —NR11R12, —O—C1-6-alkyl, C3-7-cycloalkyl, C2-alkenyl or —O—C3-7-cycloalkyl; R11 and R12 are identical or different and hydrogen, eventually substituted C1-C6-alkyl or eventually substituted aryl; R13 C1-C6-alkyl and n stands for 1, 2 or 3; means as well as their isomers and pharmaceutically acceptable salts thereof.
[0092] (29) Heterocyclic compounds ( ) in WO 95-21842 as shown in below: 40
[0093] Imidazol[1,2-a]quinoxalinone derivatives of general formula (I) wherein R1, R2, R3 are the same or independently are H, alkyl, alkoxy, halogen, NO2, NH2, CF3, CN, SO2CH3, SO2CF3, SO2NR′R″ or a 5- or 6-membered N-containing heterocyclic ring, optionally substituted, and R′, R″ are independently H or alkyl; and R4 is H or CH2—R6; and R6 is H, halogen, POR′″ R″″, NR7R8 or a 5- or 6-membered N-containing heterocyclic ring optionally substituted, and R′″, R″″ are independently hydroxy or alkoxy; and R7, R8 are the same or independently are H, (a) or alkyl optionally substituted; and n is 1, 2, or 3; (b) CH2OH, CHNOH, CN, (c) or (d) and R9 is OH, alkoxy, H or NR10R11; and R10, R11 are the same or independently are H, NH2 or OH; and X is O or S; and Y is O, S or NH2, and pharmaceutically acceptable salts thereof
[0094] (30) 1,2,4-Triazolo[4,3-a]pyrazine-4-one derivatives and their salts in WO 95-26351 as shown below: 41
[0095] 1,2,4-Triazolo[4,3-a]pyrazine-4-one derivatives having general formula (I) wherein R is N-alk, C(R4)R5, CH—R6 or C═R7. R1 and R2 are the same or different and are selected from the group consisting of hydrogen or halogen atoms or of alkyl, alkoxy, amino, —N═CH—N(alk)alk′, nitro, cyano, phenyl, imidazolyl, SO3H, hydroxy, polyfluoralkoxy, carboxy, alkoxycarbonyl, —NH—CO—NR1 R12, —N(alk)-CO—NR11R12, —N(alk-Ar)-CO—NR11R12, —NH—CS—NR11R12, —N(alk)-CS—NR11R12, —NH—CO—R11, —NH—CS—R24, —NH—C(═NR27)—NR10R12, —N(alk)-C(═NR27)—NR10R12, —Co—NR10R12, —NH—SO2—NR10R12, N(alk)-SO2—NR10R12, —NH—SO2—CF3, —NH—SO2-alk, —NR10R13, S(O)m-alk-Ar, —SO2—NR10R12, 2-oxo-1-imidazolidinyl in which position 3 may be substituted by an alkyl group, or 2-oxo-1-perhydropyrimidinyl in which position 3 may be substituted by an alkyl group, R3 is hydrogen, alkyl, cycloalkyl, alkylcycloalkyl, phenylalkyl, phenyl, Het or amino, R4 is alkyl, -alk-Het, or phenylalkyl in which the phenyl group is substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR10, and -alk-COOR10, R5 is an alkyl group (the term C1-C10 alkyl represents a straight or branched alkyl chain having one to ten carbon atoms), -alk-Het, —NR8R9, —NH—CHO, —NH—COOR17, —NH—SO2—R24, —COOR10, -alk-COOR10, -alk-CONR10R18, -alk-NR10R18, -alk-OH, -alk-CN, phenylalkyl in which the phenyl group is substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR10, and -alk-COOR10, —NH—CO—Ar in which Ar is substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR10, and -alk-COOR10, —NH—CO-Het, —NH—CO-alk-Het, —NH—CO-alk-COOR10, —NH—CO-alk-NR10R18, —NH—CO-alk-Ar in which Ar is substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR10, and -alk-COOR10, pyrrolyl-1 which may be substituted by —COOR10, —NH—CO—NH-alk-Ar in which Ar is substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR10, and -alk-COOR10, —NH—CO—NH-Het, —NH—CO—NH-alk-Het, —NH—CO—NH—Ar in which Ar may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR10, and -alk-COOR10, —NH—COalk, —NH—COcycloalkyl, —NH—CO—NH-alk or —NH—CO—NH2, or R4 and R5, together with the carbon atom they attached to, are a cycloalkyl group, R6 is hydrogen, hydroxy, alkyl (the term C1-C10 alkyl represents a straight or branched alkyl chain having one to ten carbon atoms), -alk-OH, —NR14R15, -alk-NR14R15, -alk-Het, —NH—CHO, —COO-alk, -alk —COOR10, -alk-CO—NR10R18, -phenylalkyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR10, and -alk-COOR10, R16—COOR10, —CO—COOR10 or pyrrolyl-1 possibly substituted by —COOR10.
[0096] R7 is oxygen, or NOH, NO-alk-COOR10, NO-alk, CHR19, NR10, C(COOR10) or C(CONR10R21)R20, R9 is hydrogen, alkyl, -alk-COOR10, -alk-NR10R21, -alk-Het or phenylalkyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR10, and -alk-COOR10, R9 is hydrogen or alkyl, R10 is hydrogen or alkyl, R11 is hydrogen, alkyl, (the term C1-C9 alkyl represents a straight or branched alkyl chain having one to nine carbon atoms), alkoxy, -alk-COOR10, -alk-Het, -alk-NR12R10, phenylalkyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, carboxy, alkoxycarbonyl, cyano, and -alk-COOR10, phenyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, carboxy, aloxycarbonyl, cyano and -alk-COOR10 or -Het, R12 is hydrogen or alkyl, R13 is alkyl, Het or alkoxycarbonyl, R14 and R15 are the same or different and are each an alkyl moiety, or R14 is hydrogen and R15 is hydrogen, alkyl, —COR22, —CSR23 or —SO2R24, R16 is a —CHOH— chain or —CH(OH)-alk(C1-C5), R17 is alkyl or phenylalkyl, R18 is hydrogen or alkyl, R19 is hydroxy, alkyl, -alk-Het, —NR25R26, -alk-COOR10, -Het, -phenyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, —COOR10, cyano, and -alk-COOR10, phenylalkyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, —COOR10, cyano and -alk-COOR10, R20 is hydrogen or alkyl, R21 is hydrogen or alkyl R22 is alkyl, cycloalkyl, —COOalk, -alk-COOR10, phenyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, —COOR10, cyano and -alk-COOR10, phenylalkyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, —COOR10, cyano and -alk-COOR10, -alk-NR10R12, —NH—Ar in which Ar may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, —COOR10, cyano and -alk-COOR10, phenylalkyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, —COOR10, cyano and -alk-COOR10, -Het, -alk-Het, —OR17, —NH-alk-Ar in which Ar may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, —COOR10, cyano and -alk-COOR10, —NH-alk-Het, —NH-alk, —NH2 or —NH-Het, R23 is —NH-alk, —NH—Ar, —NH-Het or —NH2, R24 is alkyl or phenyl, R25 and R26 are the same or different and are each alkyl or cycloalkyl, R27 is hydrogen or alkyl.
[0097] The term alk refers to an alkyl or alkylene moiety. The term alk′ refers to an alkyl moiety. m=0, 1 or 2. The term Ar refers to a phenyl moiety. The term Het refers to a heterocycle which is mono- or poly-saturated or unsaturated with one to nine carbon atoms and one or more heteroatom (O, S, N) which may be substituted with one or more of the following: alkyl, phenyl, or phenylalkyl.
[0098] Unless otherwise stated, in the above and below definitions, the alkyl, alkylene or alkoxy moieties are a straight or branched chain having one to six carbon atom, the acyl moieties have two to four carbon atoms, the cycloalkyl moieties have three to six carbon atoms and the halogen atoms are selected from the following: fluoride, chloride, bromide or iodide.
[0099] Preferably, Het is one of the following rings: pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, thiazolyl, oxazolinyl, thiazolinyl, pyrazinyl, tetrazolyl, triazolyl, pyrrolidinyl, piperazinyl, thienyl, furyl, azetidinyl and imidazolinyl. Each of these rings may be substituted by one or more of the following: alkyl, phenyl or phenylalyl.
[0100] The preferred substituents are methyl, phenyl or benzyl.
[0101] The preferred polyfluoroalkoxy groups are the trifluoromethoxy groups.
[0102] The compounds of the formula (I) in which R7 is NO-alk, C(COOR10)R20, C(CONR10R21)R20 or CHR19 can exist as isomers (E and Z). The compounds of the present invention include the isomers E and Z and their mixtures.
[0103] The compounds of the formula (I), in which R is CH—R6 and R6 is —CO—COOR10, can exist as tautomers (E and Z). The compounds of the present invention include the tautomers E and Z and their mixtures.
[0104] The compounds of the present invention include the eniantomers and diastereoisomers of the compounds of the formula (I), in which R is C(R4)R5 or CH—R6.
[0105] (31) Imidazo(1,2-a)indeno(1,2-e)pyrazin-4-one derivatives and their salts in WO 95-26350 as shown below: 42
[0106] Imidazo(1,2-a)indeno(1,2-e)pyrazin-4-one derivatives having general formula (I) wherein R is C═R3, C(R4)R5 or CH—R6, R1 and R2 are the same or different and are selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, amino, —N═CH—N(alk)alk′, nitro, cyano, phenyl, imidazolyl, SO3H, hydroxy, polyfluoralkoxy, —COOR7, —NH—CO—NR8R9, —N(alk)-CO—NR8R9, —N(alk-Ar)-CO—NR8R9, —NH—CS—NR8R9, —N(alk)-CS—NR8R9, —NH—CO—NR18, —NH—CS—R19, —NH—C(═NR20)—NR7R9, —N(alk)-C(═NR20)—NR7R9, —NH—SO2—NR7R9, N(alk)-SO2—NR7R9, —CO—NR7R9, —NH—SO2—CF3, —NH—SO2-alk, —NR9R11, S(O)m-alk-Ar, —SO2—NR7R9, 2-oxo-1-imidazolidinyl in which position 3 may be substituted by an alkyl group, or 2-oxo-1-perhydropyrimidinyl in which position 3 may be substituted by an alkyl group, R3 is NO-alk, CHR10, NR7, C(COOR7)R16 or C(CONR7R15)R16, R is alkyl, -alk-Het, -alk-Het″ or phenylalkyl in which the phenyl group is substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR7 and -alk-COOR7, R5 is —NR12R13, —NH—CHO, —NH—CHO, —NH—COOR17, —NH—SO2R19, —COOR7, -alk-COOR7, -alk-CONR7R15, -alk-NR7R15, -alk-OH, -alk-CN, -alk-Het″, phenylalkyl in which the phenyl group is substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR7 and -alk-COOR7, —NH—CO—Ar in which Ar is substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR7 and -alk-COOR7, —NH—CO-Het, —NH—CO-Het″, —NH—CO-alk-Het, —NH—CO-alk-Het″, —NH—CO-alk-COOR7, —NH—CO-alk-NR7R15, —NH—CO-alk-Ar in which Ar is substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR7, and -alk-COOR7, —NH—CO—C(Ar)(CF3)OCH3, pyrrolyl-1 which may be substituted by —COOR7, —NH—CO—NH-alk-Ar in which Ar is substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR7, and -alk-COOR7, —NH—CO—NH-Het, —NH—CO—NH-Het″, —NH—CO—NH-alk-Het, —NH—CO—NH-alk-Het″, —NH—CO—NH—Ar in which Ar is substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR7, and -alk-COOR7, —NH—COalk, —NH—COcycloalkyl, —NH—CO—NH-alk or —NH—CO—NH2, R6 is —NH—CHO, —COOalk, -alk-COOR7, -alk-CO—NR7R15, phenylalkyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR7, and -alk-COOR7, —R14—COOR7, —CO—COOR7, —NH—COOR17, —NH—CO—Ar in which Ar is substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR7, and -alk-COOR7, —NH—CO-Het, —NH—CO-alk-Het, —NH—CO-Het″, —NH—CO-alk-Het″, —NH—CO-alk(C2-C6)—COOR7, —NH—CO-alk(C2-C6)—NH2, —NH—CO-alk-N(alk)2, —NH—CO-alk-NH-alk, —NH—CO-alk-Ar in which Ar is substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR7, and -alk-COOR7, —NH—CO—C(Ar)(CF3)OCH3, -alk-Het″, pyrrolyl-1-may be substituted by —COOR7, —NH—CO—NH-alk-Ar in which Ar is substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR7, and -alk-COOR7, —NH—CO—NH-alk-Het, —NH—CO—NH-alk-Het″, —NH—CO—NH-Het″, or —NH—CO—NH—Ar in which Ar is substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR7, and -alk-COOR7, R7 is hydrogen or alkyl, R8 is hydrogen, alkyl, -alk-COOR7, -alk-Het″, -alk-Het, -alk-NR9R7 or phenylalkyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, —COOR7, cyano, -alk-COOR7, or phenyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, —COOR7, cyano, -alk-COOR7, -Het or -Het″, R19 is hydrogen or alkyl, R10 is -alk-COOR7, -Het″, -alk-Het″, phenyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, COOR7, cyano, -alk-COOR7, or phenylalkyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, —COOR7, cyano, -alk-COOR7, R1, is alkyl, -Het, -Het″ or alkylcarbonyl, R12 is hydrogen, alkyl, -alk-COOR7, -alk-NR7R15, -alk-Het, -alk-Het″, or phenylalkyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, carboxy, alkoxycarbonyl, cyano, and -alk-COOR7, R13 is hydrogen or alkyl, R14 is a —CHOH— or —CHOH-alk(C1-C5) chain, R15 is hydrogen or alkyl, R16 is hydrogen or alkyl, R17 is alkyl or phenylalkyl, R18 is hydrogen, or an alkyl moiety (the term C1-C9 alkyl represents a straight or branched alkyl chain having one to nine carbon atoms), alkoxy, -alk-COOR7, -alk-Het″, -alk-Het, , -alk-NR9R7, phenylalkyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, —COOR7, cyano and -alk-COOR7, phenyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, cyano, -alk-COOR7, Het or Het″, Rig is alkyl or phenyl, R20 is hydrogen or alkyl.
[0107] The term alk refers to an alkyl or alkylene moiety. The term alk′ refers to an alkyl moiety. The term Ar refers to a phenyl moiety. m=0, 1 or 2. The term Het refers to a heterocycle which is mono- or poly-saturated or unsaturated with four to nine carbon atoms and one or more heteroatom (O, S, N). The term Het″ refers to a heterocycle which is mono- or poly-saturated or unsaturated with one to three carbon atoms and one or more heteroatom (O, S, N)may be substituted with one or- or poly-saturated or insaturated with four to nine carbon atoms and one or more heteroatom (O, S, N)may be substituted with one or more of the following: alkyl, phenyl, or phenylalkyl. Provided that when R1 and R2 are hydrogen, R is CHR6, R6 is alk-Het″ in which alk is alkyl (C1) and Het″ is not 2-imidazol.
[0108] Unless otherwise stated, in the above and below definitions, the alkyl or alkylene moieties are a straight or branched chain having one to six carbon atom, the cycloalkyl moieties have three to six carbon atoms and the halogen atoms are selected from the following: fluoride, chloride, bromide, or iodide.
[0109] Preferably, Het is one of the following cycles: pyrrolyl, pyridyl, pyrimidinyl, morpholinyl, pyrazinyl, pyrrolidinyl, piperazinyl, piperidinyl, thienyl and furyl. Het″ is one of the following: pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, thiazolyl, thiazolinyl, pyrazinyl, tetrazolyl, triazolyl, oxazolyl, pyrrolidinyl, azetidinyl, piperazinyl, piperidinyl, thienyl, oxazolinyl, furyl and imidazolinyl. Each of these rings may be substituted by one or more of the following: alkyl, phenyl or phenylalkyl. The preferred substitutants are methyl, phenyl or benzyl.
[0110] The prefered polyfluoroalkoxy groups are the trifluoromethoxy groups. The compounds of the formula (I) in which R3 is NO-alk, C(COOR7)R16, C(CONR7R15)R16 or CHR10 can exist as isomers (E and Z). The compounds of the present invention include the isomers E and Z and their mixtures.
[0111] The compounds of the formula (I), in which R is CH—R6 and R6 is —CO—COOR7, can exist as tautomers (E and Z). The compounds of the present invention include the tautomers E and Z and their mixtures.
[0112] The compounds of the present invention include the eniantomers and diastereoisomers of the compounds of the formula (I), in which R is C(R4)R5 or CH—R6
[0113] The compounds of of the present invention include compounds of the formula (I) in which R, R1 and R2 are as defined previously except for when: a) R1 and R2 are hydrogen, R is CHR6, R6 is -alk-Het″ in which alk is an alkyl moiety (C1) and Het″ is a 2-imidazolyl moiety, b) R1 and R2 are hydrogen, R is CHR6, R6 is —NHCHO or alk-COOR7 in which R7 is hydrogen or a terbutyl group, c) R1 and R2 are hydrogen, R is C═R3, R3 is CHR10 and R10 is a 2-imidazolyl moiety, d) R1 is hydrogen, R2 is CHR6 and R6 is —NHCHO. The preferred compounds are those with R1 in position -7 or -8.
[0114] (32) Indeno[1,2-e]pyrazine-4-one (I) in WO 95-26349 as shown below: 43
[0115] Indeno[1,2-e]pyrazine-4-one of formula (I), wherein R is a substituted nitrogen, oxygen or sulphur atom or a radical C═R3, C(R4)R15 or CH—R6; R1 is a hydroxy radical, polyfluoroalkoxy, carboxy, alkoxycarbonyl, —NH—CHO or —NH—CO—N(alk)Ar where Ar is optionally substituted, —N(alk)-CO—NR8R9, —N(alk-Ar)-CO—NR8R9, —NH—CO—NR9R12, —NH—CS—NR8R9, —N(alk)-CS—NR8—R9, —NH—CO—R10, —NH—CS—R20, —NH—C(NR21)—NR7R9, —N(alk)-C(═NR21)—NR7R9, —NH—SO2—NR7R9, N(alk)-SO2—NR7R9, —CO—NR7R9, —NH—SO2—CF0, —NH—SO2-alk, —NR9R11, —S(O)m-alk-Ar, —SO2—NR7R9, optionally 3-substituted 2-oxo-1 imidazolidinyl or optionally 3-substituted 2-oxo-1 perhydropyrimidinyl; R2 is a hydrogen or halogen atom or an akyl radical, alkoxy, amino, —NH—CO—NH—Ar, N═CH.N(alk)alk′, nitro, cyano, phenyl, imidazolyl, acylamino, SO3H, hydroxy, polyfluoroalkoxy, carboxy, alkoxycarbonyl, —NH—CHO, —NH—CO—N(alk)Ar where Ar is optionally substituted, —N(alk)-CO—NR8R9, N(alk-Ar)—CO—NR8R9, —NH—CO—NR9R12—NH—CS—NR8R9, —N(alk)-CS—NR8R9, —NH—CO—R10, —NH—CS—R20, —NH—C(═NR21)—NR7R9, —N(alk)-C(═NR21)—NR7R9, —NH—SO2—NR7R9, —N(alk)-SO2—NR7R9, —CO—NR7R9, —NH—SO2—CF3, —NH—SO2-alk, —NR9R11, —S(O)m-alk-Ar, —SO2—NR7R9, optionally 3-substituted 2-oxo-1-imidazolidinyl or optionally 3-substituted 2-oxo-1-perhydropyrimidinyl; R3 is an oxygen atom or a NOH, NO-alk-COOX or CH—R13 radical, R4 is an alkyl radical; -alk-Het or -alk-Ar; R5 is a straight or branched C1-11 alkyl radical, -alk-Het or -alk-Ar, or R4 and R5, taken together with the carbon atom to which they are attached, form a cycloalkyl radical; R6 is a hydrogen atom radical or a hydroxy radical, straight or branched C1-11 alkyl, —NR14R15, -alk-OH, -alk-NR14R15, -alk-Ar or -alk-Het; and salts thereof
[0116] (33) Imidazo[1,2-a]pyrazine-4-one derivatives (I) in WO95-26352 as shown below: 44
[0117] Compounds of formula (I), wherein ring A is selected from rings 1, 2 and 3, wherein R is a CH2 radical or a sulphur, oxygen or nitrogen atom substituted by an alkyl radical, and salts thereof
[0118] (34) 5H-Indeno[1,2-b]pyrazine-2,3-dione derivatives and their salts (I) in WO 95-26342 as shown below: 45
[0119] 5H-Indeno[1,2-b]pyrazine-2,3-dione of formula (I), wherein R is N-alk, C(R4)R5, CH—R6 or C═R7, R1 and R2 are the same or different and are selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, amino, —N═CH—N(alk)alk′, nitro, cyano, phenyl, imidazolyl, SO3H, hydroxy, polyfluoralkoxy, carboxy, alkylcarbonyl, —NH—CO—NR11R12, —N(alk)-CO—NR11R12, —N(alk-Ar)-CO—NR11R12, —NH—CS—NR11R12, —N(alk)-CS—NR11R12, —NH—CO—NR1, —NH—CS—R24, —NH—C(═NR27)—NR10R12, —N(alk) C(═NR27)—NR10R12, —CO—NR10R12, —NH—SO2—NR10R12, N(alk)-SO2—NR10R12, —NH—SO2—CF3, —NH—SO2-alk, —NR10R13, S(O)m-all-Ar, —SO2—NR10R12, 2-oxo-1-imidazolidinyl in which position 3 may be substituted by an alkyl group, or 2-oxo-1-perhydropyrimidinyl in which position 3 may be substituted by an alkyl group, R3 is oxygen, NOH, NOalk or NOalkAr, R4 is alkyl, -alk-Het or phenylalkyl in which the phenyl group is substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR10, and -alk-COOR10, R5 is an alkyl group (the term C1-C11 alkyl represents a straight or branched alkyl chain having one to eleven carbon atoms), -alk-Het, NR8R9, —NH—CHO, —NH—COOR17, —NH—SO2R24, —COOR10, -alk-COOR10, -alk-CONR10R18, -alk-NR10R18, -alk-OH, -alk-CN, phenylalkyl in which the phenyl group is substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR10, and -alk-COOR10, —NH—CO—Ar in which Ar is substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR10, and -alk-COOR10, —NH—CO-Het, —NH—CO-alk-Het, —NH—CO-alk-COOR10, —NH—CO-alk-NR10R18, —NH—CO-alk-Ar in which Ar is substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR10, and -alk-COOR10, pyrrolyl-1 wich may be substituted by —COOR10, —NH—CO—NH-alk-Ar in which Ar is substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR10, and -alk-COOR10, —NH—CO—NH-Het, —NH—CO—NH-alk-Het, —NH—CO—NH—Ar in which Ar is substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR10, and -alk-COOR10, —NH—COalk, —NH—COcycloalkyl, —NH—CO—NH-alk or —NH—CO—NH2, or R4 and R5, together with the carbon atom they attached to, are a cycloalkyl group, R6 is hydrogen, hydroxy, alkyl (the term C1-C11 alkyl represents a straight or branched alkyl chain having one to eleven carbon atoms), -alk-OH, —NR14R15, -alk-NR14R15, alk-Het, —NH—CHO, —COOalk, -alk-COOR10, -alk-CO—NR10R18, phenylalkyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR10, and -alk-COOR10, —R16—COOR10, —CO—COOR10 or pyrrolyl-1 may be substituted by —COOR10, R7 is oxygen or NOH, NO-alk-COOR10, NO-alk, CHR19, C(COOR10)R20 or C(CONR10R21)R20, R is hydrogen, alkyl, -alk-COOR10, -alk-NR10R21, -alk-Het or phenylalkyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, —COOR10 and -alk-COOR10, R9 is hydrogen or alkyl, R10 is hydrogen or alkyl, R11 is hydrogen, alkyl (the term C1-C9 alkyl represents a straight or branched alkyl chain having one to nine carbon atoms), alkoxy, -alk-COOR10, alk-Het, -alk-NR12R10, phenylalkyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, carboxy, alkoxycarbonyl, cyano and -alk-COOR10, phenyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, carboxy, alkoxycarbonyl, cyano and -alk-COOR10 or -Het, R12 is hydrogen or alkyl, R13 is alkyl, Het or alkoxycarbonyl, R14 and R15 are the same or different and are each an alkyl group or R14 is hydrogen and R15 is hydrogen, alkyl, —COR22, —CSR23 or SO2R24, R16 is a —CHOH or —CH(OH)alk(C1-C5) chain, R17 is alkyl or phenylalkyl, R18 is hydrogen or alkyl, R19 is hydroxy, alkyl, alk-Het, —NR25R26, -alk-COOR10, -Het, phenyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, —COOR10, cyano, and -alk-COOR10 or phenylalkyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, —COOR10, cyano, and -alk-COOR10, R20 is hydrogen or alkyl, R21 is hydrogen or alkyl, R22 is alkyl, cycloalkyl, —COOalk, -alk-COOR10, phenyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, —COOR10, cyano, and -alk-COOR10, phenylalkyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, —COOR10, cyano, and -alk-COOR10, -alk-NR10R12, —NH—Ar in which Ar may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, —COOR10, cyano, and -alk-COOR10, -phenylalkyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, —COOR10, cyano, and -alk-COOR10, -Het, -alk-Het, —OR17, —NH-alk-Ar in which Ar may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, —COOR10, cyano and -alk-COOR10, NH-alk-Het, —NH-alk, —NH2 or —NH-Het, R23 is —NH-alk, —NH—Ar, —NH-Het or —NH2, R24 is alkyl or phenyl, R25 and R26 are the same or different and are each alkyl or cycloalkyl, R27 is hydrogen or alkyl.
[0120] The term alk refers to an alkyl or alkylene group. The term alk′ refers to an alkyl group. m=0, 1 or 2. The term Ar refers to a phenyl group. The term Het refers to a heterocycle which is mono or poly saturated or unsaturated with four to nine carbon atoms and one or more heteroatom (O, S, N) may be substituted with one or more of the following: alkyl, phenyl, or phenylalkyl. Provided that when R1 and R2 are hydrogen and R3 is oxygen, R is not (a) C═R7 in which R7 is oxygen or NOH, (b) CH—R6 in which R6 is hydroxy.
[0121] Unless otherwise stated, in the above and below definitions, the alkyl or alkylene groups are a straight or branched alkyl chain having one to six carbon atom, the acyl groups have two to four carbon atoms, the cycloalkyl groups have three to six carbon atoms and the halogen are of the following: fluoride, chloride, bromide, or iodide.
[0122] Preferably, Het is one of the following rings: pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, oxazolinyl, thiazolinyl, pyrazinyl, tetrazolyl, triazolyl, pyrrolidinyl, piperazinyl, piperidinyl, thienyl, furyl, azetidinyl, imidazolinyl. Each of these rings may be substituted by one or more of the following: alkyl, phenyl or phenylalkyl. The preferred substituents are methyl, phenyl or benzyl.
[0123] The preferred polyfluoroalkoxy groups are the trifluoromethoxy groups. The compounds of the formula (I) in which R is C═R7, with R7 being NO-alk, C(COOR10)R20, C(CONR10R21)R20 or CHR1G and/or with R3 being NOH, NOalk or NOalkAr, can exist as isomers (E and Z). The compounds of the present invention include the isomers E and Z and their mixtures.
[0124] The compounds of the formula (1), in which R is CH—R6 and R6 is CO—COOR10, can exist as tautomers (E and Z). The compounds of the present invention include the tautomers E and Z and their mixtures. The compounds of the present invention include the enantiomers and diastereoisomers of the compounds of the formula (I), in which R is C(R4)R5 or CH—R6.
[0125] (35) Quinazoline-2,4-dione (I) in WO 95-19346 as shown below: 46
[0126] Compounds of formula I wherein R is (C1-6 alkyl or phenyl optionally mono-, di- or trisubstituted by halogen, (C1-4)alkyl, (C1-4)alkoxy, nitro, trifluoromethyl, amino, (C1-4)alkylamino, di(C1-4)alkylamino, cyano, (C1-4)alkylsulfonyl, phenylsulfonyl or sulfonylamino, R1 and R2 independently are hydrogen, hydroxy, (C1-4)alkyl, (C1-4)alkoxy, (C2-5)alkenyl, halogen, trifluoromethyl, nitro, amino, (C1-4)alkylamino, benzyloxy, benzoylamino, carboxy, cyano, (C1-4)alkoxy-carbonyl, (C1-4)alkylsulfonyl, phenylsulfonyl, sulfonylamino, (C2-5)alkanoylamino or phenyl optionally substituted by (C1-4)alkyl, halogen or nitro, provided that R1 and R2 are not both hydrogen if R is unsubstituted phenyl, or R1 and R2 on adjacent carbon atoms together form a group —CH═CH—CH═CH—, or a salt thereof. Alkyl and alkoxy groups and moieties in the compounds of formula I may be straight—or branched-chained. Halogen means fluorine, chlorine, bromine or iodine. The compounds of formula I may form cationic salts, e.g. alkali metal or ammonium salts deriving from the sulfonamido group or when a carboxyl group is present. Depending on the nature of the substituents defined *above, the compounds of formula I may also form acid addition salts. The tautomeric forms of the compounds of formula I are also embraced.
[0127] (36) 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide-3-carboxylic acid derivatives (I) in WO 95-07899 as shown in below: 47
[0128] Compounds of formula (I) wherein R1 is a carboxy, alkoxycarbonyl, tetrazolyl, —CO—NH2, —CO—NH-alk, —CO—N(alk)2—CO—NHOH, —CO—N(alk)OH, —CO—NH—O—R10, —CO—N(alk)-OR10 radical or a group convertible in vivo into a carboxy radical, R2, R3 and R4, which are the same or different, are hydrogen or halogen atoms or alkyl or alkoxy radicals, R5 is a hydroxy, —NHOH, —NH—CO—NH2, —CH2—NH2, hydroxyalkyl, alkoxyalkyl, or -alk=NOH radical, R6, R7, R8 and R9, which are the same or different, are hydrogen or halogen atoms or alkyl, alkoxy, polyfluoroalkyl, amino, nitro, cyano, vinyl, polyfluoroalkoxy, alkoxycarbonyl, carboxy, phenylalkyloxy, phenylalkyl, benzoylamino,phenylcarbonyl, hydroxy, —NHOH, —NH—CO—NH2, —CH2—NH2, hydroxyalkyl, alkoxyalkyl, -alk=NOH or phenoxy, with the phenyl ring being optionally substituted by one or several substituents selected from the halogen atoms and the alkyl, alkoxy or polyfluoroalkyl radicals, R10 is an alkyl or phenylalkyl radical and alk is an alkyl or alkylene radical. The invention also concerns the salts of thereof, the preparation thereof, and drugs containing same.
[0129] (37) Imidazo(1,2-a)pyrazin-4-one derivatives (I) in WO95-02602 as shown below. 48
[0130] Compounds of formula (I), wherein R is an oxygen or sulphur atom or an NH or N-alk radical, and each of R1 and R2, which are the same or different , is a hydrogen or halogen atom or an alkyl, alkoxy, amino, acylamino, —NH—CO—NH—Ar, —N═CH—N(alk)alk′, nitro, cyano, phenyl, imidazolyl or SO3H radical, the preparation thereof, and drugs containing such compounds.
[0131] (38) 2,3-Benzodiazepine derivatives (I) and (II) in GB 2 311 779 A as shown below. 49
[0132] Non-competitive AMPA antagonistic compounds of the formula I, wherein R1 and R2 represent, independently, a hydrogen, a halo, a C1-4 alkyl group, a C1-4 alkoxy group, a nitro group, a trifluoromethyl group or a group of the formula —NR8R9, wherein R8 and RX stand, independently, for a hydrogen, a C1-4 alkyl group or a group of the formula —COR10, wherein R10 is a hydrogen, a C1-6 alkyl group that can be substituted, a C6-10 aryl group, a C1-4 alkoxy group, a C3-5 cycloalkyl group, a C2-6 alkenyl group a C3-5 cycloalkoxy group or a group of the formula —NR11R12, wherein R11 and R12 mean, independently, a hydrogen, a C1-4 alkyl group, a C3-5 cycloalkyl group or a C6-10 aryl group, R3 represents a C1-4 alkyl groups a C3-5 cycloalkyl group or a group of the formula —CO—R13, wherein R13 has the same definitions given in relation to R10, R4 and R5 mean, independently, a hydrogen or a C1-3 alkyl group, R6 and R7 are, independently, a hydrogen, a chloro or a bromo, with the provision that if one of R6 and R7 stands for a hydrogen, the other is different from hydrogen, as well as the isomers thereof and the acid addition salts of the compounds or the isomers.
[0133] (39) Tetramic acid derivatives (I) in GB 2 266 888 A as shown below: 50
[0134] Wherein R1 and R2 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, —ORa, —SRa, —SORa, —SO2Ra, —SO2NRaRb, —NRaRb, —NRaCORb, —NRaCO2Rb, —CORa, —CO2Ra or —CONR8Rb; or R1 and R2 together represent the residue of a carbocyclic or heterocyclic ring; R3 and R4 independently represent hydrogen, hydrocarbon, a heterocyclic group, trifluoromethyl, —ORc, —SRc, —SORa, —SO2Ra, —SO2NRaRb, —CORa, —CO2Ra or —CONRaRb, provided that R3 does not represent C2-5 alkoxycarbonyl when R4 represents an optionally substituted phenyl group; Ra and Rb independently represent hydrogen, hydrocarbon or a heterocyclic group; and Rc represents hydrocarbon or a heterocyclic group.
[0135] (40) Pyrrolo-pyridazinone derivatives (I) in GB 2 265 372 A as shown below: 51
[0136] Pyrrolo-pyridazinone derivatives, wherein R1 and R2 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, —ORa, —SRa, —SORa, —SO2Ra, —SO2NRaRb, —NRaRb, —NRaCORb, —NRaCO2Rb, —CORa, —CO2Ra or —CONRaRb; or R1 and R2 together represent the residue of a carbocyclic or heterocyclic ring; R3, R4 and R5 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, —ORa, —SRa, —SORa, —SO2Ra, —SO2NRaRb, —NRaRb, —NRaCORb, —NRaCO2Rb, —CORa, —CO2Ra or CONRaRb; and Ra and Rb independently represent hydrogen, hydrocarbon or a heterocyclic group.
[0137] (41) 2-Phenylpyridazino[4,5-b]indole-1,4-dione derivatives (1) in GB 2 290 292 A as shown below: 52
[0138] Compound of formula I, or a salt or prodrug thereof: wherein R1 and R2 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, —ORa, —SRa, —SORa, —SO2Ra, —SO2NRaRb, —NRaRb, NRaCORb, —NRaCO2Rb, —CORa, —CO2Ra or —CONRaRb; or R1 and R2 together represent the residue of a carbocyclic or heterocyclic ring; R3, R4, R5 and R6 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, ORa, —SRa, —SORa, —SO2Ra, —SO2NRaRb, —NRaRb, —NRaCORb, —NRaCO2Rb, —CORa, —CO2Ra or —CONRaRb; and Ra and Rb independently represent hydrogen, hydrocarbon or a heterocyclic group.
[0139] (42) Arylthioxaline derivatives (I) in Tokkaihei 8-59660 as shown below: 53
[0140] Arylthioxaline derivatives of the formula (I) and its related salts, wherein R1 is hydrogen, halogen, or nitro, R2 is hydrogen, halogen, nitro, cyano, or trihalogenomethyl, R3 is hydrogen, halogen, or nitro, R4 is hydrogen, optionally substituted lower alkyl, or optionally substituted lower cycloalkyl, and Ar is optionally substituted aromatic heterocyclic ring having at least one nitrogen atom.
[0141] (43) Hydroxyquinoxalinedione derivatives in Tokkaihei 7-165756 as shown below: 54
[0142] The present invention relates to hydroxyquinoxalinedione derivatives of the above formula and its related salt, wherein R1 is hydrogen or lower alkyl, and R2 is nitro or trifluoromethyl.
[0143] (44) Imidazo[1,2-a]pyrazin-4-one (I) in WO 95-02601 as shown below: 55
[0144] Compounds of formula (I), wherein either R is C═R3, C(R4) R5 or CH—R6, R1 and R2 are hydrogen, halogen, alkyl, alkoxy, amino, acylamino, —NH—CO—NH—Ar, —N═CH—N(alk)alk′, nitro, cyano, phenyl, imidazolyl or SO3H, R3 is oxygen, NOH, NO-alk-COOK or CH—R7, R4 is alkyl, -alk-Het or alk-Ar, R5 is alkyl, -alk-Ar, or C(R4)R5 is cycloalkyl, R6 is hydroxy, alkyl, NR8R9, -alk-OH,-alk-NR8 R9, -alk-Ar or -alk-Het, R7 is hydroxy, alkyl, phenyl, -alk-Ar, -alk-Het, NR10 R11 or a heterocyclic ring, R8 and R9 are alkyl, or R is hydrogen and R9 is hydrogen or alkyl, —COR12, —CSR30 or —SO2 R13, R10 and R11, are alkyl or cycloalkyl, R12 is alkyl, cycloalkyl, phenyl, —COO-alk, —CH2—COOX, —CH2—NH2, —NH-alk, —NH—Ar, —NH2 or —NH-Het, R13 is alkyl or phenyl, R30 is —NH-alk, —NH—Ar, —NH2 or —NH-Het; or R is a 2-imidazolylmethyl radical and each of R1 and R2 is a hydrogen atom.
[0145] (45) AMPA antagonists (1) in WO 94-26747 as shown below: 56
[0146] Compounds having formula (I) or a pharmaceutically acceptable salt thereof wherein R1 is hydrogen, alkyl, or benzyl; X is O or NOR2, wherein R2 is hydrogen, alkyl or benzyl; Y is N—R4 wherein R4 is hydrogen, OH or alkyl; n is 0 or 1; R6 is phenyl, naphthyl, thienyl, pyridyl, all of which may be substituted one or more times with substituents selected from the group consisting of halogen; CF3, NO2, ammo, alkyl, alkoxy and phenyl; A is a ring of five to seven atoms fused with the benzo ring at the positions marked a and b.
[0147] (46) 2,3-Disubstituted-(5,6)-heteroarylfused-pyrimidine-4-ones in EP 0807 633 A2 as shown below: 57
[0148] 2,3-Disubstituted-(5,6)-heteroaryl fused-pyrimidine-4-ones of formula (I) and their salts are new: ring A=a group of formula (i) or (ii) both optionally substituted by H, 1-6C alkyl, halo, CF3, (CH2)nNH2, (1-6C alkyl)amino(CH2)p, di(1-6C alkyl)amino(CH2)n, 1-6C alkoxy, 1-6C hydroxyalkyl, (1-6C alkyl)O(1-6C alkyl), CN, (1-6C alkyl)COO(1-6C alkyl), (1-6C alkyl)OCOO(1-6C alkyl), (1-6C alkyl)COO, OH, NO2, R3CO, R4OCO, di(1-6C alkyl)NCO, 1-6C cycloalkyl, R4NHCO or phenyl (optionally substituted); A, B, D, E=C or N; F, G. J=C, N, O or S with proviso; R1=Ph1 or pyridin-2-yl, pyridin-3-yl or pyridinyl optionally substituted; Ph1=a group of formula (iii); R2=Ph2 or a group of formula (Iv) or (v); K, L, M=C or N provided that only one is N; P, Q, T=C, N, O or S provided that only one can be O or S and that at least one is a heteroatom; Ph2=a group of formula (vi); R3, R4═H or 1-6C alkyl; R5H, 1-6C alkyl, halo, CF3, 1-6C alkoxy or 1-6C alkylthio; R6—R8═H or halo; R9 e.g. H, 1-6C alkyl (optionally substituted), halo, CF3, 1-6C alkoxy (optionally substituted), 1-6C alkylthio, (CH2)pOR13, (CH2)NH(1-6C alkyl), (CH2)nN(1-6C alkyl)2, (CH2)pNH(1-5C cycloalkyl) (sic), (CH2)pCONH2, (CH2)n—CONH(1-6C alkyl), (CH2)pCON(1-6C alkyl)2, (CH2)pCONH(1-5C cycloalkyl) (sic), (CH2)pCOOR3, (1-6C alkyl)OCO(1-6C alkyl), (1-6C alkyl)OCOO(1-6C alkyl), OCO(1-6C alkyl), (CH2)pNHCO(1-6C alkyl) or CN; R10, R14=e.g. H, 1-6C alkyl (optionally substituted), halo, CF3, 1-6C alkoxy (optionally substituted), 1-6C alkylthio, (CH2)pOR13, (CH2)nNH(1-6C alkyl), (CH2)pN(1-6C alkyl)2, (CH2)pNH(1-5C cycloalkyl) (sic), COO(CH2)pR4, (CH2),NH2, 1-6C hydroxyalkyl, (1-6C alkyl)O(1-6C alkyl), CHO or CN; R , R12═H or halo; R13═H, 1-6C alkyl, CO(1-6C alkyl), COO(1-6C alkyl), CONH(1-6C alkyl) or CON(1-6C alkyl)2; R15—R17=H, CN, 1-6C alkyl, halo, CF3, CHO or 1-6C alkoxy; n, p=0-3; provided that when R9═H then one of R11 and R12 is not H.
[0149] (47) Quinoxaline compounds (I) in EP 0 511 152 A2 as shown below: 58
[0150] Quinoxaline compounds having the formula I wherein R1 is H, NO2, CN, CF3 or halogen, le and R3 independently are H, CN, CF3, halogen, C(NOH) C1-6-alkyl, COR4 or SO2R4 wherein le is C1-6-alkyl-, optionally substituted, or NR5R6 wherein R5, R6 independently are H, C3-6-cycloalkyl, is C1-6—, optionally substituted, compositions thereof and methods of preparing the compounds are described.
[0151] (48) Hydrazone derivatives in EP 0 503 349 A1 as shown below: 59
[0152] Hydrazone derivatives having the formula (I) wherein n is 0 or 1; R1 is hydrogen, C1-6-alkyl which may be branched, C3-7-cycloalkyl, benzyl, phenyl which may be substituted, acyl, hydroxy, C-6-alkoxy, CH2CO2 R: is hydrogen or C1-6-alkyl which may be branched, CH2CN, CH2CONRIVRV wherein RIV and RV independently are hydrogen or C1-6-alkyl, or CH2C(═NOH)—NH2; R2 is pyridyl or phenyl, both of which may be substituted one or more times preferably into the ortho and para positions with halogen, CF3, NO2, CN, phenyl, SO2NR″R′″ wherein R″ and R′″ independently are hydrogen, benzyl, or C1-6-alkyl; R5, R6, R7 independently are hydrogen, C1-6-alkyl which may be branched, phenyl, halogen, C1-alkoxy, NO2, CN, CF3, or SO2NR11R12 wherein R11 and R12 independently are hydrogen, benzyl, or C1-6-alkyl; or R6 and R7 together form an additional 4 to 8 membered carbocyclic ring which may be aromatic or partial saturated and which may be substituted with halogen, NO2, CF3, CN, SO2NR13 R14 wherein R13 and R14 independently are hydrogen, benzyl, or C1-6-alkyl; and R4 and R5 have the meanings set forth above; or R4 and R5 together form an additional 4 to 8 membered carbocyclic ring whihc may be aromatic or partial saturated and which may be substituted with halogen, NO2, CF3, CN, SO2NR13 R14 wherein R13 and R14 independently are hydrogen, benzyl, or C-6-alkyl; and R6 and R7 have the meanings set forth above.
[0153] (49) Dihydro-2,3-benzodiazepine derivatives (I) in EP 0 699 676 A1 as shown below: 60
[0154] Dihydro-2,3-benzodiazepine derivatives represented by the formula I wherein R is methyl, X is acetyl and Aryl is p-nitrophenyl.
[0155] (50) Oxopyridinylquinoxaline derivatives (I) in EP 0 676 397 A1 as shown below: 61
[0156] An oxopyridinylquinoxaline derivative represented by the following formula I or pharmaceutically acceptable salts thereof wherein R1 is hydrogen, halogen, nitro or trihalomethyl; R2 is hydrogen, halogen, nitro, cyano, trihalomethyl, carbamoyl, carbomoyl substituted with lower alkyl, sulfamoyl, or sulfamoyl substituted with lower alkyl; R3 is hydrogen, nitro, or halogen; R4 is hydrogen, lower alkyl, substituted lower alkyl, lower cycloalkyl, or substituted lower cycloalkyl; R5's are substituents independently selected from the group consisting of halogen, nitro, cyano, lower alkyl, carbamoyl, and carbamoyl substituted with lower alkyl; and n is an integer of 0 to 4.
[0157] (51) Dioxo-tetrahydroquinoline derivatives (IA) in EP 0 459 561 A2 as shown below: 62
[0158] Dioxo-tetrahydroquinoline derivatives of formula (IA), wherein R1 is a group of part formula (I) and (II); wherein U and V independently represent cyano, carboxy, —COR6, —CO2 R6, —CO2 SR6, —CONHOH or —CONHNH2; n is zero or 1, preferably zero; T represents cyano, carboxy, —COR6, —CO2 R6, —CONHOH or —CONHNH2 or a group of formula in which the broken circle represents two non-adjacent double bonds in any position in the five-membered ring; B represents a bond or a carbonyl group (C═O); W, X Y and Z represent oxygen, sulphur, nitrogen or carbon, provided that no more than one of W, X, Y and Z represents oxygen or sulphur, at least one of W, X, Y and Z represents carbon and at least one of W, X, Y and Z is other than carbon; one of E, F and G represents nitrogen or carbon and the remainder represent carbon; A1, A2 and A3 represent one, two or three substituents not exceeding the maximum number permissible by the disposition of heteroatoms in the five- or six-membered ring, which substituents are independently selected from hydrogen, hydrocarbon, halogen, cyano, trifluoromethyl, nitro, —ORa, —SRa, —SORa, —SO2 Ra, SO2 NRaRb, —NRaRb, —NRaCORb, —NRaCO2Rb, CORa, —CO2Ra or —CONRaRb; or A1 and A2 or A2 and A3 together represent the residue of an aromatic or heteroaromatic ring; R2, R3, R4 and R5 independently represent hydrogen, hydrocarbon, halogen, cyano, trifluoromethyl, nitro, —ORa, —SRa, —SORa, —SO2Ra, SO2NRaRb, —NRaRb, —NRaCORb, —NRaCO2Rb, CORa, —CO2 Ra or —CONRaRb; or R2 and R3, R3 and R4 or R4 and R5 together represent the residue of an aromatic or heteroaromatic ring; R6 represents hydrocarbon; and Ra and Rb independently represent hydrogen or hydrocarbon.
[0159] (52) Quinoxaline derivatives in EP 0 377 112 A1 as shown below: 63
[0160] Heterocyclic dihydroxyquinoxaline compounds having the formula wherein R1 is hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkylalkoxy, cycloalkoxy, or acyloxy; and R5, R6, R7 and R8 independently are hydrogen, NO2, halogen, CN, SO2 NR′R′, SO2 R′, CF3, or OR′, wherein R′ is hydrogen or C1-4-alkyl.
[0161] (53) Quinoxaline derivativess in EP 0 374 534 A1 as shown below: 64
[0162] Heterocyclic dihydroxyquinoxaline compounds having the formula wherein R1 is hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkylalkoxy, cycloalkoxy, or acyloxy; R5 and R6 together form a further fused ring, which may be substituted with hydrogen, halogen, or CN, and R7 and R5 independently are hydrogen, NO2, halogen, CN, SO2 NR′R′, SO2R′, CF3, or OR′, wherein R′ is hydrogen or C1-4-alkyl; or R7 and R8 together form a further fused ring, which is substituted with hydrogen, halogen, or CN, and R5 and R6 independently are hydrogen, NO2, halogen, CN, SO2NR′R′, SO2R′, CF3, or OR′, wherein R′ is hydrogen or C1-4-alkyl.
[0163] (54) Quinoxaline derivatives in EP 0 315 959 A2 as shown below: 65
[0164] Heterocyclic dihydroxyquinoxaline compounds having the formula wherein R1 is C1-12-alkyl, which may optionally be substituted by hydroxy, formyl, carboxy, carboxylic esters, amides or amines, C3-8 cycloalkyl, aryl, aralkyl; and wherein R6 is hydrogen, halogen, CN, CF3, NO2, or OR′, wherein R′ is C1-4-alkyl and R5, R7 and R8 is hydrogen, provided R6 is not CF3, OCH3, NO2, CL or Br when R1 is CH3; or R6 and R7 independently are NO2, halogen, CN, CF3, or OR′, wherein R′ is C1-4-alkyl and R5 and R8 are each hydrogen; or R5 and R6 together form a further fused aromatic ring, which may be substituted with halogen, NO2, CN, CF3 or OR′, wherein R′ is C1-4-alkyl, and R7 and R8 independently are hydrogen, halogen, CN, CF3, NO2 or OR′, wherein R′ is C4-alkyl; or R7 and R8 together form a further fused aromatic ring, which may be substituted with halogen, NO2, CN, CF3 or OR′, wherein R′ is C1-4-alkyl, and R5 and R6 independently are hydrogen, halogen, CN, CF3, NO2 or OR′, wherein R′ is C1-4-alkyl.
[0165] (55) Heterocyclic compounds in EP 0348 872 A1 as shown below: 66
[0166] Heterocyclic dihydroxyquinaoxaline compounds having the formula wherein R1 and R2 independently are hydrogen, NO2, NH2, CN, halogen, SO2NH2; —X-Y-Z- is selected from —N═N—NR3—, —NR3—N═N—, ═N—NR3—N═, —S—CH═N—, —N═CH—S—, —CH═C(CO2 R3)—S—, —S—C(CO2 R3)═CH—, =N—Se—N═, —N—CR3—NR3—, —NR3—CR3═N—, =NON═, —N═CR3—CR3═N—, —NH—CR3═CR3—CR3═N—, —N═CR3—CR3═CR3—NH, ═N—S—N═; wherein R3 is hydrogen, lower alkyl, CF3.
[0167] (56) Heterocyclic dihydroxyquinoxaline derivatives in U.S. Pat. No. 4,812,458 as shown below: 67
[0168] Heterocyclic dihydroxyquinoxaline compounds having the formula wherein R1 is halogen, CN, CF3, ethynyl, or N3 and R2 is SO2C1-3-alkyl, CF3, NO2, ethynyl, or CN.
[0169] (57) Pyrrolyl tetrahydrobenzoquinoxalinedione (I) in WO 96-11922 as shown below: 68
[0170] Pyrrolyl tetrahydrobenzoquinoxalinedione of formula I and their tautomeric and isomeric forms, as well as the pharmaceutically acceptable salts thereof, wherein R1 hydrogen; an aliphatic residue with 1 to 6 C-atoms, which can carry one or two different substituents of the formula —COOR4, —CONHR4, —CO—R4, —OR4, —NHR4, —NH—CO—R4, —CONH—SO2R4 or NHSO2R4, of which R4 means hydrogen, C1-C4-alkyl, phenyl, benzyl, 1-phenylethyl or 2-phenylethyl, wereby the phenyl rings in R4 can be substituted by 1, 2 or 3 of the following substituents: C1-C4-alkyl, CF3, C1-C4-alkoxy, F3CO, halogen, nitro, CN, —OH, —CONHR5 and/or —COOR5 (R5 hydrogen, C1-C4-alkyl, phenyl or benzyl); —O—R6, of which R6 is hydrogen or an aliphatic residue with up to 4 C-atoms which can carry one of the following residues: —COOR4, —CONHR4, —NHCOR4, —NHSO2R4, —OH or phenyl; R2 hydrogen, C1-C4-alkyl or phenyl; R3 hydrogen or the residue —(CH2)m-R7, whereby m is the number 0, 1, 2, 3 or 4 and R7 hydrogen, C1-C4-alkyl, phenyl, phenylsulfonyl, NO2, CN, —COO—(CH2), —R8, —CONH—(CH2)n—R8, —CONHSO2R4, —CO—R8, —CH═CH—CONHR8, —CH═CH—COOR8, —CH═NOR8, —CH2—NR8R9, CH2NH—CY—(CH2)nR9, CH2NH—CY—X—(CH2)n-R9, CH2NH—CO—CF3, CH2NH—SO2—R9 wereby X and Y independently of each other are oxygen or NH, n is the number 0, 1, 2, 3 or 4, R8 means hydrogen or linear or branched C1-C4-alkyl, which can be substituted by one or two phenyl- or pyridyl-residues, and R9 means hydrogen, linear or branched C1-C6-alkyl, phenyl or pyridyl, wereby all phenyl or pyridyl residues contained in R8 and R9 can carry one or two of the following residues: O—C1-C4-alkyl, F, Cl, Br, J, C1-C4-alkyl, NO2, CF3, —COOR5, —CONHR5, NH2, CN, —SO2phenyl, —NHSO2R5, —NHCOR5, OH, —SO2—C1-C4-alkyl, —NHCOCF3, —SO2R5 and —OCF3.
[0171] (58) Amido-quinoxalinedione (I) in WO 95-35289 as shown below: 69
[0172] Amido-quinoxalinedione derivatives of formula (I), their tautomers, isomers and enantiomers, and their salts in which R1═H or 1-4C alkyl; n=0-1; m=0-4; R2═H, 1-6C alkyl or phenyl (optionally mono- or di-substituted with 14C alkyl, OR6, NH2, NO2, NHCOR6, CN, CF3, OCF3, CO2R6, F, Cl, Br, I, COR6 or SO2R6); R3=F, Cl, Br, I, 1-4C alkyl, OR7, COR7, NH2, NO2, NHCOR7, CF3, CN; R4, R5═H, 1-4C alkyl, I-4C alkoxy, CF3, OCF3, F, Br, I, NO2, CN or an annellated benzene ring (optionally mono or di-substituted with up to 2 1-4C alkyl, 1-4C alkoxy, CF3, OCF3, F, Br, I, NO2, CN); R6═H, 14C alkyl, phenyl or benzyl; R7═H, 1=4C alkyl or CF3; R8═H, 1-4C alkyl, phenyl, phenylsulphonyl, NO2, CN, COO(CH2)rR, CONH(CH2)rR, COR, CH═CHCONHR, CH2NRR′, CH2NHCY(CH2)rR, CH═CHCOOR, CH═NOR, CH═NR, CH2NHCY-Z(CH2)rR′, CH2NHCOCF3 or a gp. of formula (b)-(f); R9=H or 1-4C alkyl; R═H, 14C alkyl, phenyl, benzyl, pyridyl or benzhydryl; R′═H, 1-4C alkyl, Ph, pyridyl or 4-(R-substituted)-piperidin-1-yl; Y═O or N; Z=O or NH; r=0-4; q=0-2; the benzene rings in R8, R and R′ are optionally mono- or di-substituted with NH2, OMe, OEt, Cl, Br, OCF3, F, Me, Et, NO2, COOR1, CONHR1, CH2NHR1, CH2NHCOCF3, CH2NHCOMe, NHSO2Me, NHCOMe or NHCOCF3.
[0173] (59) Acid amide derivatives (I) in WO 95-31443 as shown below: 70
[0174] Acid amides of the formula wherein R1 represents hydrogen or nitro, R2 and R3 stand, independently from each other, for hydrogen, lower alkyl or lower alkenyl optionally carrying a substituent selected from the group consisting of halogen, hydroxy, lower alkoxy, di(lower alkyl) amino, phenyl-lower alkoxycarbonyl and a 5- to 6-membered saturated hetero-ring containing 1 or 2 nitrogen and/or oxygen atom (s); or R2 and R3 form, together with the adjacent nitrogen atom, a 6-membered saturated heterocyclic group containing optionally 1 or 2 additional nitrogen atoms and/or oxygen atoms (s), said ring optionally carrying a hydroxy or a hydroxy-lower alkyl group; and all of the possible mesomers, tautomeric forms and stereoisomers of the acid amides of the formula (I) and the mixtures thereof
[0175] (60) Quinoxalindione derivatives (I) in WO 97-19066 as shown below: 71
[0176] Quinoxalindione derivatives of formula (I), their isomers and salts are new: R1═—(CH2)n—CR2H—(CH2)m-Z; R5=1-6C alkyl or 2-6C alkenyl (both optionally substituted by Q), SOpR13 or —CH═R15; Q=halo, OR8, NR9R10, SO0R11 or COR12; or aryl or heteroaryl (both optionally substituted); R6, R7═H, halo, NO2, CN, NR16R17, COR14 or OR18; or aryl or heteroaryl (both optionally substituted); 1-6C alkyl or 2-6C alkenyl (both optionally substituted by Q), SOpR13 or —CH═R15; R2═H or —(CH2)qR3; R3═H. OH, 1-6C alkoxy or NR19R20; n, m, q=0-3; Z=POXY, OPOXY, SO2R21COOR22, CN or tetrazolyl; R8, R18═H or 1-6C alkyl (optionally halo substituted); o, p=0-2; R11, R13═H, 1-6C alkyl or optionally substituted aryl; R12, R14, R21═OH, 1-6C alkoxy or NR23R24; R15═O, ═NOH or a group of formula (a): X, Y═OH, 1-6C alkoxy, 1-4C alkyl or NR25R26; R9 and R10, R16 and R7, R19 and R20, R23 and R24, R25 and R26═H, 1-4C alkyl, aryl, or together with the N atom form a 5-7 membered saturated heterocycle (optionally containing an additional O, S or N and optionally substituted), or an unsaturated 5-membered heterocycle containing 1-3 N and optionally substituted; provided that R5 is not CF3 or Me.
[0177] (61) N-substituted fused azacycloalkylquinoxalinediones (I) in WO 96-28445 as shown below: 72
[0178] In formula (I) m and n are independently 0, 1 or 2 provided that m+n is >1. R1 is hydrogen, an alkyl or an alkylaryl; X and Y are independently hydrogen, halogen, nitro, cyano, trifluoromethyl, COOH, CONR4R5, SO2CF3, SO2R4, SONR4R5, alkyl, alkenyl, (CH2)zCONR4R5, (CH2)zCOOR4, or NHCOR4, wherein R4 and R5 are independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl or alkylaryl, and z is an integer from 0 to 4; R2 is alky COOR3, alkylamine, alkyquanidine, aryl, alkylaryl, COalkyl, COalkylaryl, CONR3alkyl, CONR3aryl, CONR3alkylaryl, CSNR3alkyl, CSNR3alkylaryl or a common amino acid moiety joined by an amide bond, wherein R3 is hydrogen, alkyl or alkylaryl.
[0179] (62) Spiro[heterocycle-imidazo[1,2-a]indeno[1,2-e]pyrazine]-4′-ones (1) in WO 96-14318 as shown below: 73
[0180] Compounds of formula (I), wherein R3 and R4, taken together with the carbon atom to which they are attached, form (a) a 2- or 3-pyrrolidine ring, a 2- or 4-piperidine ring or a 2-azacycloheptane ring, said rings being optionally substituted at the nitrogen atom by an alkyl radical, —CHO, —COOR11, —CO-alk-COOR6, —CO-alk-NR6 R12, —CO-alk-CONR6R8, —CO—COOR6, —CO—CH2—O—CH2—COOR6, —CO—CH2—S—CH2—COOR6, —CO-alk, —CO—Ar11. —CO-alk-Ar11, —CO—NH—Ar11, —CO—NH-alk-Ar11, —CO-Het, —CO-alk-Het, —CO—NH-Het, —CO—NH-alk-Het, —CO—NH2, —CO—NH-alk, —CO—N(alk)alk′, —CS—NH2, —CS—NH-alk, —CS—NH—Ar11, —CS—NH-Het, -alk-Het, -alk-NR6 R8, -alk-Ar11, —SO2-alk, SO2—Ar or —CO-cycloalkyl, where the cycloalkyl is optionally 2-substituted by a carboxy radical; or (b) a 2-pyrrolidine-5-one ring.
[0181] (63) 5H,10H-Imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one derivatives (I) in WO 97-25327 as shown below: 74
[0182] Compounds of formula (I), wherein R is a hydrogen atom or a —COOH or CH2OH radical, R1 is a —CH—R2 radical, R2 is a 3-dimethyl-1H-pyrazole-4-yl, 4-chloro-1-methylimidazole-5-yl or 3-hydroxy-isoxazole-5-yl radical except for 10-(1,3-dimethyl-1H-pyrazole-4-methylene)-5H, 10H-imidazo[1,2-a]indeno [1,2-e]pyrazine-4-one, isomers thereof, salts thereof, the preparation thereof and drugs containing said compounds.
[0183] (64) 5H,10H-Imidazo[1,2-a]indolo[3,2-e]pyrazine-4-one derivatives (I) in WO 97-25329 as shown below: 75
[0184] Compounds of formula (I) wherein R is a hydrogen atom or an -alk-COOH radical, racemic mixtures, enantiomers and diastereoisomers thereof, salts thereof, the preparation thereof and drugs containing said compounds.
[0185] (65) 5H,10H-Imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one derivatives (I) in WO 97-25328 as shown below: 76
[0186] Compounds of formula (1), wherein R is a hydrogen atom or a —COOH, -alk-COOH, —PO3H2, CH2—PO3—H2 or —CH═CH—COOH radical, or a phenyl radical substituted by a carboxy radical, R1 is an alk-CN, -alk-COOH, alk-Het, alk-PO3H2 or -alk-CO—NH—SO2R2 radical, R2 is an alkyl or phenyl radical, alk is an alkyl radical, Het is a saturated or unsaturated mono- or polycyclic heterocyclic ring containing 1-9 carbon atoms and one or more heteroatoms selected from O, S and N, said heterocyclic ring optionally being substituted by one or more alkyl, phenyl or phenylalkyl radicals, with the proviso that when R is a hydrogen atom or a —COOH or —PO3H2 radical, R1 cannot be -alk-COOH, isomers, racemic, mixtures, enantiomers and diastereoisomers thereof, salts thereof, the preparation thereof, intermediates thereof and drugs containing said compounds.
[0187] (66) 2-Substituted 5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-ones (1) in WO 97-25326 as shown below: 77
[0188] Compounds of formula (I), wherein R is a —CO—CH2—PO3H2, —CO—NH-tetrazole-5-yl, —CO—NHOH, CO—NH—NH2, -alk-COOH, -alk-COOalk′, —CH2—PO3H2, —CO—NH—SO2—R1 or —CH═CH—COOH radical, or a phenyl radical substituted by a carboxy radical, alk and alk′ are an alkyl radical and R1 is an alkyl, trifluoromethyl or phenyl radical optionally substituted by a carboxy or alkoxy-carbonyl radical, racemic mixtures, isomers, enantiomers and diastereoisomers thereof, salts thereof, the preparation thereof and drugs containing said compounds.
[0189] (67) Indeno[1,2-e]pyrazine-4-ones (I) in WO 97-10246 as shown below: 78
[0190] Compounds of formula (I), wherein R is a C═CH—R2, C(R3) R4, CH—NH2, CH—CH(OH)—COOH or CH—CH(OH)—COOalk radical, R1 is an alk-NH2 or alk-NH—CO—R5 radical, R2 is a —COOH or —COOalk radical, R3 is an alkyl, -alk-Ar or -alk-Het radical, R4 is an NH2, —NH-alk, —N(alk)-alk′, —NH—CO-alk, —NH—CO—Ar′, —NH—CO-ALK-Ar′, —NH—CO-Het, —NH—CO-alk-Het, —NH—CO-alk-COOH, —NH—CO-alk-COOalk′, -alk-COOH, -alk-COOalk′, —NH—CO—NH2, —NH—CO—NH-alk or —NH—CO—NH—Ar′ or —NH—CO—NH-alk-Ar′ radical, or R3 and R4, together with the carbon atom to which they are attached, form a 2- or 3-pyrrolidine, 2- or 4-piperidine or 2-azacycloheptane substituted or unsubstituted ring, R5 is an —NH2, —NH-alk, —NH—Ar′, —NH-cycloalkyl, —NH-alk-Ar′ or —N(alk)-alk′ radical, the salts thereof, the preparation thereof and medicaments containing same.
[0191] (68) 5H,10H-Imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one derivatives (I) in WO 96-31511 as shown below: 79
[0192] Compounds of formula (I), wherein R is a hydrogen atom or a carboxy, alkoxycarbonyl, —CO—NR4, R5, —PO3H2 or —CH2OH radical and R1 is an alk-NH2, -alk-NH—CO—R3, -alk-COOR4, -alk-CO—NR5 R6 or —CO—NH—R7 radical.
[0193] (69) Decahydroisoquinoline compounds (I) in U.S. Pat. No. 5,356,902 as shown below: 80
[0194] Compound of the formula (I) wherein: R1 is hydrogen, C1-10 alkyl, arylalkyl, alkoxycarbonyl, aryloxycarbonyl or acyl; R2 is hydrogen, C1-C6 alkyl, substituted alkyl cycloalkyl, or arylalkyl; R3 is a group of the formula; R4 is hydrogen, C1-4 alkyl, CF3, phenyl, bromo, iodo, or chloro; or a pharmaceutically acceptable salt thereof
[0195] (70) Phosphonoalkylquinolin-2-ones in U.S. Pat. No. 5,342,946 as shown below: 81
[0196] Having the general formula: wherein n is 0, 1, 2 or 3; R1 and R2 are selected from the group consisting of hydrogen, halogen, halomethyl, nitro, amino, alkoxy, hydroxyl, hydroxymethyl, C1 to C6 lower alkyl and C7 to C12 higher alkyl, aryl, and aralkyl; and the pharmaceutically acceptable salts thereof.
[0197] (71) Imidazobenzodiazepine compounds (I) in U.S. Pat. No. 5,270,306 as shown below: 82
[0198] Compound having the formula: wherein R3 is hydrogen, C1-8-alkyl which may be branched, or cycloalkylmethyl; R7 and R8 are independently hydrogen, halogen, CF3, CN, NO2, NH2, C1-4-alkyl or C1-4-alkoxy; and R4 is hydrogen and R5 is hydrogen or C1-7 alkyl; or R4 and R1 together signify (CH2), wherein n is an integer of 2-3.
[0199] (72) Isatine derivatives in U.S. Pat. No. 5,192,792 as shown below: 83
[0200] Indole-2,3-dione-3-oxime compound having the formula wherein R1 is hydrogen, C1-6-alkyl which may be branched, C3-7-cyclo-alkyl, benzyl, phenyl which may be substituted, acyl, hydroxy, C1-alkoxy, CH2 CO2 R″ wherein R′ is hydrogen or C1-alkyl which may be branched, CH2CN, CH2CONRIVRV wherein RIV and RV independently are hydrogen or C1-alkyl, or CH2C(═NOH)NH2; R2 is (1) alkenyl of from two to six carbon atoms, preferably alkyl, (2) alkynyl of from two to six carbons, preferably propargyl, (3) (CH2)1-6 CO2H, (4) (CH2)1-6 CONHR wherein R is C1-6 alkyl, optionally branched; aryl which is phenyl optionally substituted by one or more of lower alkyl of from one to four carbons, halogen wherein halogen is fluoro, chloro, bromo, or iodo, trifluromenthyl, cyano, carboxy, alkoxycarbonyl wherein the alkoxy is of from one to four carbons, alkylthio wherein the alkyl is of from one to four carbons, nitro, acyl of from two to four carbons, hydroxy, C1-6-alkoxy, CH2CO2 R′ wherein R′ is hydrogen or C1-alkyl which may be branched, CH2CN, CH2CONRIVRV wherein RIV and RV independently are hydrogen or C1-6alkyl, optionally branched; aralkyl which is aryl as defined above attached through C1-4 alkyl, or SO2 R10 wherein R10 is C1alkyl, optionally branched; aryl which is phenyl optionally substituted by one or more of lower alkyl of from one to four carbons, halogen wherein halogen is fluoro, chloro, bromo, or iodo, tri-fluoromethyl, cyano, carboxy, alkoxycarbonyl wherein the alkoxy is of from one to four carbons, alkylthio wherein the alkyl is of from one to four carbons nitro, acyl of from two to four carbons, hydroxy, C1-6 alkoxy, CH2CO2 R′ wherein R′ is hydrogen or C1-4-alkyl which may be branched, CH2CN, CH2CONRIVRV wherein RIV and RV independently are hydrogen or C1-6 alkyl, optionally branched; aralkyl which is aryl as defined above attached through C1-4 alkyl; R4, R5, R6, R7 independently are hydrogen, C1-6 alkyl, which may be branched, phenyl, halogen, C1-6-alkoxy, NO2, CN, CF3, or SO2NR′″R′″ wherein R″ and R″″ independently are hydrogen, or C1-alkyl; or R6 and R7 together form an additional 4 to 7 membered ring which may be aromatic or partial saturated and which may be substituted with halogen, NO2, CF3, CN, SR2NR′″R″′ wherein R and R independently are hydrogen, or C1-6-alkyl; and R4 and R5 have the meanings set forth above.
[0201] (73) Aryl-spaced decahydroisoquinoline-3-carboxylic acids in U.S. Pat. No. 5,446,051: 84
[0202] Preferably, the compounds are of the general formula (I) wherein R1 is H, C1-C10-alkyl, arylalkyl, alkoxycarbonyl, aryloxycarbonyl, or acyl; R2 is H, C1-C6-alkyl, substituted alkyl, C4-C7 cycloalkyl or arylalkyl; R3 is aryl, arylalkyl, heterocycle, substituted heterocycle, C4-C7 cycloalkyl or C4-C7 cycloalkenyl; P4 is CO2H, SO3H, PO3H2, or one of the following cyclic compounds: wherein R5 is H, C1-6-alkyl or aryl; m=0, 1 or 2; and n=0, 1 or 2; or a pharmaceutically acceptable salt thereof
[0203] (74) Quinoxalindione derivatives reported in WO 94-25469 and shown below: 85
[0204] Quinoxalindione derivatives represented by the above formula wherein R1 is (CH2), —CR2H—(CH2)m-Z and R5, R6, R7 and R8 together or independently are hydrogen, C1-C6 alkyl, CF3, nitro, halogen, NR9R10, cyano, SOpR11, SO2NR12R13, SO3H, SO3C1-6alkyl or OR14; R2 is hydrogen, or (CH2)q—R3; R3 is hydrogen, OH, C1-6-alkoxy or NR15R16, and n, m and q are 0, 1, 2, or 3; Z is POXY, OPOXY, OR17, NR18R19, NH—COR20, NH—SO2R21, SO2R22, CO2R23, halogen, cyano or tetrazole; R11 is hydrogen, C1-C6 alkyl, phenyl; p is 0, 1, or 2; R12, R13, R17 or R23 is hydrogen or C1-C4 alkyl; R14 is hydrogen or 1-3 halogen substituted C1-C6 alkyl; R20 and R21 are C1-C6 alkyl or halogen substituted phenyl or hetaryl; R22 is OH, C1-C6 alkoxy or NR24R25; X and Y are together or independently OH, C1-C6 alkoxy, C1-C4 alkyl or NR18R19; R9 and R10 are together or independently hydrogen, CO-C1-C6 alkyl, phenyl or C1-C6 alkyl, which may be substituted with C1-C4 alkoxy or C1-C4 alkyl mono- or disubstituted NH2 group, or together with the nitrogen form a 5-7 membered heterocyclic ring which may contain additional N, S or O and can be substituted, or form five membered heterocyclic ring which may contain 1-3 nitrogens and can be substituted; R15 and R16, R18 and R19 together or independently are hydrogen, C1-C4 alkyl, phenyl or together with the oxygen form 5-7 membered heterocyclic ring which may contain additional N, S or O and can be substituted, or form five membered heterocyclic ring which may contain 1-3 nitrogens and can be substituted; R24 and R25 together or independently are hydrogen, C1-C4 alkyl, or together with the oxygen form 5-7 membered heterocyclic ring which may contain additional N, S or O, and their isomers and salts and provided R2 is hydrogen and Z POXY or CO2R23 then R5-R8 is not hydrogen; and provided R2 is hydrogen, Z POXY or CO2R23 and R5, R6, R7 and R8 are CF3, NO2, halogen, NH2 or methyl, the compounds of the above formula are double-substituted and provided R1 is methanophosphonic acid and R6 cyano or substituted imidazole then together R5, R7 and R8 is not hydrogen and provided R1 is methanosulphonic acid and R6 is CF3 or NO2 and R7 is imidazole, R5 and R8 is not hydrogen; and provided R1 is CH2—COOH and R5 and R8 is hydrogen, R6 and R7 is not halogen or methyl; and the pharmaceutically acceptable salts thereof.
[0205] (75) Isoquinolinyl-carboxylic acid compounds reported in U.S. Pat. No. 5,606,062 and shown below: 86
[0206] Isoquinolinyl-carboxylic acid compounds represented by the above formula wherein R1 is hydrogen, C1-C10 alkyl, arylalkyl, alkoxycarbonyl, or acyl; R2 is hydrogen, C1-C6 alkyl, substituted alkyl, cycloalkyl, or arylalkyl; R3 is CO2H SO3H, CONHSO2R8, or a group of formula: 87
[0207] W is (CH2)n, S, SO, SO2; Y is CHR7, NR4, O, S, SO, or SO2; Z is NR6, CHR7, or CH; or W and Y together are HC═CH or C_C, or Y and Z together are HC═CH or C≡C; R4 is hydrogen, C1-C4 alkyl, phenyl, or acyl; R5 is hydrogen, C1-C4 alkyl, CF3, phenyl, hydroxy, amino, bromo, iodo, or chloro; R6 is acyl; R7 is independently hydrogen, C1-C4 alkyl, phenyl, or substituted phenyl; R8 is C1-C4 alkyl or tetrazole-5-yl; and n is 0, 1, or 2; provided that when Y is NR4, O, S, SO, or SO2, W is (CH2)n and Z is CHR7 or CH; further provided that when W is S, SO, or SO2, Y is CHR7, Z is CHR7 or CH or Y and Z together are HC═CH or C≡C; further provided that when W and Z are CH2, Y is not S; further provided that when W and Y together are HC═CH or C≡C, Z is CHR7; and the pharmaceutically acceptable salts thereof.
[0208] (76) Decahydroisoquinoline compounds described in U.S. Pat. No. 5,527,810 as shown below: 88
[0209] Decahydroisoquinoline represented by the above formula wherein R1 is hydrogen, C1-C10 alkyl, arylalkyl, alkoxycarbonyl, aryloxycarbonyl or acyl; R2 is hydrogen, C1-C6 alkyl, substituted alkyl, cycloalkyl, or arylalkyl; R3 is a group of the formula: 89
[0210] R4 is hydrogen, C1-C4 alkyl, CF3, phenyl, bromo, iodo, or chloro, and the pharmaceutically acceptable salts thereof
[0211] (77) Cycloalkynoxalinediones shown in U.S. Pat. No. 5,721,234 as exemplified below: 90
[0212] Cycloalkynoxalinediones represented by the above formula wherein Z is an alicyclic fused ring having 5 to 7 carbon atoms; R1 is hydrogen, an alkyl or an arylalkyl; X and Y are independently hydrogen, halogen, nitro, cyano, COOH, CONR2R3, SONR2R3 wherein R2 and R3 are independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl or aralkyl; and A is O, CH2, NR4, CH2NR4, CN, tetrazole or CO wherein R4 is hydrogen, alkyl, hydroxyalkyl, aminoalkylamine or aralkyl, wherein (i) when A is O, CH2, NR4, or CH2NR4 then B is hydrogen, alkyl, alkenyl, aryl, aralkyl, hydroxyalkyl, alkoxy, aminoalkyl, heterocyclic, alkylheterocyclic, heterocyclic-methyl, heterocyclic-ethyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heterocyclic-carbonyl, alkylheterocyclic-carbonyl, any of which may be unsubstituted or substituted by one or more hydroxy, CO2H, mercapto, amino, alkyl or butoxycarbonyl group, CONR5R6 wherein R5 is hydrogen, alkyl having 1 to 6 carbon atoms, or aralkyl, and R6 is alkyl, aryl, or aralkyl, or N, R5, and R6 taken together form a cyclic amine, or when A is NR4 or CH2NR4 then B is a common amino acid moiety joined by an amide bond or B joins with R4 and the nitrogen to form a four to seven membered heterocyclic ring, provided that when Z is a fused cyclohexyl ring and R4 is hydrogen then B is not hydrogen; (ii) when A is CN then B is not present and Z is not a fused cyclohexyl ring; (iii) when A is tetrazole then B is hydrogen or alkyl having 1 to 6 carbon atoms; and (iv) when A is CO then B is hydroxy, alkoxy, aralkoxy, alkyl having 1 to 6 carbon atoms, aralkyl, NR7R8 wherein R7 is hydrogen, alkyl having 1 to 6 carbon atoms, or aralkyl, and R8 is alkyl, aryl, or aralkyl, or N, R7, and R8 taken together from a cyclic amine, and the pharmaceutically acceptable salts thereof.
[0213] (78) Phosphonoalkylquinolin-2-ones as reported in U.S. Pat. No. 5,510,338 and shown below: 91
[0214] Phosphonoalkylquinolin-2-ones represented by the above formula wherein n is 0, 1, 2 or 3. R1 or R2 are selected from the group consisting of hydrogen, halogen, halomethyl, nitro, amino, alkoxy, hydroxyl, hydroxymethyl, C1 to C6 lover alkyl and C7 to C12 higher alkyl, aryl, and aralkyl; and the pharmaceutically acceptable salts thereof.
[0215] (79) 2,3-Benzodiazepine derivatives (1) and (II) in P 97 00688 as shown below: 92
[0216] 2,3-Benzodiazepine derivatives and medicinal preparations containing such drugs represented by the formula I wherein R1 and R2 can be, independently from each other, hydrogen, halogen, alkyl group with 1-4 carbonic atoms, alcoxy group with 1-4 carbonic atoms, nitro group, trifluoromethyl group, or group having a general structure of —NR8R9, where the meaning of R8 and R9, can be, independently from each other, hydrogen, alkyl group with 1-4 carbonic atoms, or group having a general structure of —COR10, where R10 means hydrogen atom, alkyl group with 1-6 carbonic atoms substituted in given cases, aryl group with 6-10 carbonic atoms, alcoxy group with 14 carbonic atoms, cycloalkyl group with 3-5 carbonic atoms, alkenyl group with 2-6 carbonic atoms, cycloalcoxy group with 3-5 carbonic atoms, or group having a general structure of —NR11R12, where the meaning of R11 and R12, independently from each other, hydrogen atom, alkyl group with 1-4 carbonic atoms, cycloalkyl group with 3-5 carbonic atoms, or aryl group with 6-10 carbonic atoms, the meaning of R3 can be alkyl group with 14 carbonic atoms, cycloalkyl group with 3-5 carbonic atoms, or group having a general structure of —CO—R13, where the meaning of R13 can be the same as given for R10, the meaning of R4 and R5, can be, independently from each other, hydrogen atom, or alkyl group with 1-3 carbonic atoms, the meaning of R6 and R7, can be, independently from each other, hydrogen atom, Cl atom, or Br atom, with the condition that if any of R4 or R5 means hydrogen atom, the second can only be other than hydrogen atom, further, the isomers, salts obtained with acid addition, and the medicinal preparations originating from them.
[0217] 2,3-Benzodiazepine derivatives represented by the formula II wherein R1, R2, R4, R5, R6 and R7 is given for general structure (I).
[0218] (80) Oxadiazole derivatives (I) in DE 196 43 037 A1 as shown below: 93
[0219] Oxadiazole derivatives of formula (I), and their racemates, enantiomers, diastereomers, mixtures and acid addition salts, are new. One of X, Y═N and the other=O; Z=pyridyl substituted by Si, or Ar (optionally substituted by R2 and R3); Ar=phenyl substituted at the 2-position by S1 and optionally at the 6-position by S2; or Ar=phenyl substituted at the 3- or 4-position by S2; S1=B-V-D-R4, B-N(D-R4)D-R41 or a group of formula (a) (optionally substituted by halo, oxo, OR7, OCOR7, 1-4C alkyl, 2-6C alkenyl or 2-6C alkynyl); S2=B-V-D-R4 or B-N(D-R4)D-R41; V, E=O, S or NR7; D=1-10C alkylene, 2-10C alkenylene or 2-10C alkynylene (all optionally substituted by Q1); B=bond or as for D; n, m=1-3, and n+m is at least 2; R1=1-10C alkyl, 2-1 C alkenyl or 2-10C alkynyl (all optionally substituted by one or more Q2), a norbornane, norbornene, di(3-6C)cycloalkyl-methyl, adamantane or noradamantane residue (all optionally substituted by 1-4C alkyl), H, phenyl (optionally substituted by 1-3 Q3 (directly or via 1-4C alkylene)), phenyl (substituted by B-N(D-R4)DR41, B-V-D-R4, OCH2O or OCH2CH2O), A″-A′, 3-7C cycloalkyl (optionally substituted by Q2), fluorenyl, a [3.3.0]bicyclooctane group; or an optionally substituted group of formula (b)-(d); y=1 or 2; z=0-2; R2, R3=1-10C alkyl, 2-10C alkenyl or 2-10C alkynyl (all optionally substituted by Q2), 5H, NR56, halo, NO2, CF3, OR7, SR7, COOR7, 6-10C aryl, aryl(1-6C)alkyl or 6-10C aryloxy; or R2+R3 complete an unsaturated fused 5-7 membered ring (optionally containing one or more heteroatoms, and optionally substituted by OR7, NR5R6, halo, CN, NO2, CF3, COOR7, 1-10C alkyl, 2-10C alkenyl or 2-10C alkynyl; R4, R41=1-10C alkoxy, 2-10C alkenyloxy or 2-10C alkynyloxy (all optionally substituted by Q2), OH, halo, NO2, CF3, CN, SH, 1-6C alkylmercapto, A-Ar, OAr′, Ar′-substituted 1-6C alkoxy, M′, NR5R6 or 3-8C cycloalkoxy (optionally substituted by oxo, OR7 or OCOR7); R5, R6=1-10C alkyl, 2-10C alkenyl or 2-10C alkynyl (all optionally substituted by OH, optionally substituted phenyl, optionally substituted benzyl, NR7R71 or 1-8C alkoxy), H, optionally substituted 3-6C cycloalkyl or 6-10C aryl (optionally substituted by halo, OR7, 1-4C alkyl, NR7R71, SO3H or COOR7); or NR5R6=an optionally unsaturated 5-6 membered ring, optionally containing other heteroatoms, and optionally substituted by Q4; R7, R7═H, R, 2-4C alkenyl, 24C alkynyl, or benzyl or phenyl (both optionally substituted by OH, C1, Br or OMe); R8=1-4C alkyl, 2-4C alkenyl, 2-4C alkynyl, phenyl, benzyl or 3-6C cycloalkyl; R9═H, 1-4C alkyl, COOR7, CH2OR7, CONR5R6 or phenyl; Q1=CN, CHO, COOR7, CONHSO2R7, CONR5R6, CH═NOR7, COR8, CH(OR7)R8, CH(OR7)OR7′, CH═CHR9, NR5R6, NHCOR7, NHCONR5R6, NHCOOR7, OR7, OCOR7, OCOOR7, OCONR5R6, SR7, SOR7, SO2R7, SO3H, SO2NR5R6, halo, 1,3-dioxolan or 1,3-dioxan); Q2=oxo or Q1; A″=1-6C-alkyl, 2-6C alkenyl or 2-6C alkynyl; A=H or as for A″; A′=phenyl (optionally ring substituted, directly or via a 1-4C alkylene bridge, by one or more groups Q3), 3-7C cycloalkyl (optionally ring substituted, directly or via a 1-4C alkylene bridge, by one or more groups Q2), M, CONHM or NHCOM; Ar′=aryl substituted by one or more Q3; M′=5-7 membered heterocycle linked via C, containing one or more heteroatoms, optionally substituted by benzyl, 14C alkyl, halo, OR7, CN, NO2, NH2, SO2R7 or CONR5R6 (sic)); M=heterocycle as for M′, (which may also be linked by N, and also be substituted by optionally substituted phenyl or substituted benzyl); Q3=halo, 1-4C alkyl, CF3, CHO, COOR7, CONHSO2R7, CONR5R6, CH═NOR7, COR8, CH(OH)R8, CH(OR7)OR71, CH═CHR9, NR5R6, NO2, 1-4C alkyl-NR5R6, NHCOR17, NHCONR5R6, NHCOOR7, NH—SO2R7, OR7, OCOR7, OCONR5R6, SR7, SOR7, SO2R , SO3H or SO2NR5R6; Q4=1-4C alkyl, (CH2)n-Q5, halo, OR7, CN, NO2, NR7R7, SO3H, COOR7, CONR7R71, SO2R7, oxo or a ketal; Q5=phenyl, NH2, 1-4C alkylamino, di(1-8C)alkylamino or NHCOOR7; heteroatoms ═N, O, S.
[0220] (81) Quinoxalindione derivatives reported in WO 96-37500 and shown below: 94
[0221] Quinoxalindione derivatives represented by the formula I wherein R1 is —(CH2)nCR2H—(CH2)m-Z and R5, R6, R7 and R8 together or independently are hydrogen, C1-6-alkyl in which one or more hydrogen atoms are replaced with halogen atoms, nitro, halogen, (CH2)q—R3; R3 hyrdogen, hydroxy, C1-6-alkoxy or NR15R16; n, m and q can be 0, 1, 2 or 3; Z is POXY, OPOXY, SO2R17, COR18, halogen, cyano or tetrazole; R11 H, C1-6 alkyl, phenyl; p 0, 1 or 2; R12 and R13 are independently hydrogen or C1-4alkyl; R14 A-R19, or means C6-12-aryl- or hetaryl, which can be substituted with halogen, C1-6-alkoxy, hydroxy, cyano, NR20R20, eventually with halogen substituted C1-6alkyl and/or COR22 and A linear or branched, saturated or unsaturated alkyls with C1-20-carbon atoms in which one or several carbons can be substituted by O, S and/or NR26 and can be substituted with halogen; and R19 hydrogen, NR24R25, halogen, C1-6-alkyl which eventually is substituted with halogen, C1-4alkoxy, COR23, CN or one C6-12-aryl or hetaryl which is substituted with halogen, and/or substituted COR22; and R18 hydrogen, C1-4-alkyl, hydroxy, C1-6-alkoxy or NR27R28; R17, R22 and R23 hydroxy, C1-6-alkoxy or NR29R30, R26 hydrogen, C1-6-alkyl, C1-6-alkenyl, X and Y are similar or different and are hydroxy, C1-6-alkoxy, C1-4-alkyl or NR27R28; R9 and R10, R20 and R21 and/or R25 and R24, are similar or different and hydrogen, CO—C1-6-alkyl, phenyl or C1-6-alkyl, which with C1-4-alkoxy or one eventually with C1-4-alkyl mono- or di-substituted amino group substituted is, or together with nitrogen atom bild 5-7-membered saturated heterocyclic ring, which may contain additional N, S- or O-atom and can be substituted, or bild 5-membered saturated heterocyclic ring, which contains 1-3 N atoms and can be substituted; R15 and R16, R27 and R28, R29 and R30 are similar or different and are hydrogen, C1-4-alkyl, phenyl or bild together with nitrogen atom 5-7-membered saturated heterocyclic ring, which may contain additional O—, S—, N-atom and can be substituted or bild 5-membered saturated heterocyclic ring, which can contain 1-3 nitrogen atoms and can be substituted, although R5—R8 always mean OR14, and R14 does not mean H or eventuall 1-3 halogen substituted C1-6-alkyl.
[0222] AMPA and/or Kainate Receptor Channel Blocker
[0223] The inhibitors of the present invention also include AMPA and/or kainate receptor channel blockers. The term “AMPA and/or kainate receptor channel blockers” is used to refer to moieties that reduce the permeability of channels associated with the AMPA and/or kainate receptor to cations (preferably to Na+,K+ and/or Ca2+ ions).
[0224] AMPA and/or kainate receptor channel blockers can therefore be used to prevent a signal being transmitted due to ionic flux that would otherwise occur when glutamate binds to the AMPA and/or kainate receptor.
[0225] AMPA and/or kainate receptor channel inhibitors include e.g. fluorowillardiine and Joro spider toxin.
[0226] Having described the inhibitors of the present invention, their therapeutic uses will now be discussed in greater detail.
[0227] Therapeutic Uses
[0228] Inhibitors of the present invention may be used in human and veterinary medicine. Treatments may be prophylactic or may be in respect of existing conditions.
[0229] As explained supra, the inhibitors may be used in the manufacture of a medicament for treating a demyelinating disorder. The term “demyelinating disorder” is used herein to include any disorder that results in a reduced level of myelination.
[0230] Demylinating disorders include acute disseminated encephalomyelitis, acute demyelinating polyneuropathy (Guillain Barre syndrome), chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, Marchifava-Bignami disease, central pontine myelinolysis, Devic syndrome, Balo disease, HIV- and HTLV-myelopathy, and progressive multifocal leucoencephalopathy.
[0231] Demylinating disorders also include secondary demyelinating disorders—i.e. where bystander myelin loss occurs as a consequence of a secondary pathological insult.
[0232] Examples of secondary demyelinating disorders are CNS lupus erythematodes, polyarteriitis nodosa, Sjögren syndrome, sarcoidosis and isolated cerebral vasulitis.
[0233] The present invention includes within its scope pharmaceutically acceptable compositions useful in treating demyelinating disorders which comprise an inhibitor of the present invention. The inhibitor will usually be provided in combination with a pharmaceutically acceptable carrier. It may be used in any suitable form, provided that it can still act in inhibiting the interaction of glutamate with the AMPA and/or kainate receptor complex. For example, pharmaceutically acceptable salts, esters, hydrates, etc. may often be used.
[0234] Pharmaceutical compositions within the scope of the present invention may include one or more of the following: preserving agents, solubilising agents, stabilising agents, wetting agents, emulsifiers, sweeteners, colorants, odourants, salts, buffers, coating agents or antioxidants.
[0235] They may contain a further therapeutically active agent in addition to an inhibitor of the present invention. The further therapeutically active agent may be an immunosuppresive agent (e.g. corticotrophin, a glucocorticoid, cyclophosphamide, cyclosporine, azothioprine or mitozantrone), an interferon (IFN; IFN-beta-1a e.g. Rebif and Avonex; IFN-beta-1b e.g. Betaseron and Betaferon; IFN-alpha-2a e.g. Alphaferone; IFN-alpha-2b e.g. Viraferon), a phosphodiesterase type IV inhibitor, a humanised monoclonal antibody against a leukocyte adhesion molecule (e.g. Antegran), a synthetic polypeptide (e.g. glatiramer acetate, copolymer-1) a tissue matrix metalloproteinase (MMP) inhibitor (e.g. hydroxamic acid-based inhibitors of MMPs) or a tumour necrosis factor (TNF) inhibitor (e.g. Thalidomide or TNF-receptor immunoglobulin fusion protein).
[0236] The combination of an inhibitor of the present invention and a further therapeutically active agent may be used simultaneously, seperately or sequentially to treat a demyelinating disorder. It may provide synergistically effective combination. The further therapeutically active agent may be an immunosuppresive agent (e.g. corticotrophin, a glucocorticoid, cyclophosphamide, cyclosporine, azothioprine or mitozantrone), an interferon (IFN; IFN-beta-1a e.g. Rebif and Avonex; IFN-beta-1b e.g. Betaseron and Betaferon; IFN-alpha-2a e.g. Alphaferone; IFN-alpha-2b e.g. Viraferon), a phosphodiesterase type IV inhibitor, a humanised monoclonal antibody against a leukocyte adhesion molecule (e.g. Antegran), a synthetic polypeptide (e.g. glatiramer acetate, copolymer-1) a tissue matrix metalloproteinase (MMP) inhibitor (e.g. hydroxamic acid-based inhibitors of MMPs) or a tumour necrosis factor (TNF) inhibitor (e.g. Thalidomide or TNF-receptor immunoglobulin fusion protein).
[0237] A pharmaceutical composition within the scope of the present invention may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) routes. Such a composition may be prepared by any method known in the art of pharmacy, for example by admixing one or more active ingredients with a suitable carrier. Preferably it will be provided in unit dosage form. It will normally be provided in a sealed, sterile container e.g. in an an ampoule, a vial a bottle, a blister pack, etc.
[0238] Different drug delivery systems can be used to administer pharmaceutical compositions of the present invention, depending upon the desired route of administration. Such systems include tablets, capsules, lozenges, pastilles, powders, solutions, suspensions, syrups, ointments, pastes, oils, aerosols, suppositories, enemas, pessaries, tampons, sprays, nebulizers, injectable compositions, etc.
[0239] Dosages of the inhibitors of the present invention can vary between wide limits, depending upon the nature of the treatment and the age and condition of the individual to be treated. However, a daily dosage of from 0.5 mg to 1000 mg, preferably of from 50-200 mg may be suitable. The dosage may be repeated as often as appropriate. If side-effects develop, the amount and/or frequency of the dosage can be reduced, in accordance with good clinical practice.
[0240] The therapeutic uses of the present invention are based upon animal models that are discussed in the examples and that are believed to be reliable. Prior to the present invention there was no disclosure of the use of antagonists of the present invention for treating demyelinating disorders. Only limited characterisation studies of kainate and AMPA receptors had been performed. Matute et al had performed various studies. For example in PNAS 95, 10229-10234, 1998 (which was published after the earlier priority date of the present application) studies acute and chronic kainate excitotoxic damage to the optic nerve are reported.
[0241] The present invention will now be described by way of example only, with reference to the accompanying drawings, wherein:
[0242] FIG. 1 shows that the AMPA receptor antagonist NBQX reduces severity of paralysis during EAE in rats. NBQX (30 mg/kg i.p. twice daily; 10-16 dpi) significantly reduces the peak disease score. Data represent the mean±SEM of disease score (n=10/group).
[0243] FIG. 2 shows that NBQX (30 mg/kg i.p. twice daily; 10-16 dpi) reduces weight loss during the course of EAE in rats prior to cessation of treatment (16 dpi). Data represent the mean±SEM of disease score (n=10/group).
[0244] FIG. 3 shows that the non-competitive AMPA antagonist GYKI53773 reduces the severity of paralysis during EAE. GYKI53773 (30 mg/kg i.p. twice daily; 10-16 dpi) significantly reduces the peak disease score. Data represents the mean±sem of disease score, standardised to days after disease onset (&Circlesolid; Vehicle n=9; ◯GYKI53773 n=10).
[0245] FIG. 4 shows that the AMPA receptor antagonist NBQX reduces the severity of paralysis during chronic EAE. In A, NBQX, 30 mg/kg (◯; n=10) and vehicle (&Circlesolid;; n=9) were administered i.p. twice daily for 7 days starting on day 10 post immunisation (10-16 dpi; stippled bar). In B, NBQX, 30 mg/kg kg (◯; n=7) and vehicle (&Circlesolid;; n=10) were administered i.p. once daily for 17 days commenced on dpi 26 (2642 dpi; hatched bar). Data represents the mean±sem of disease score.
[0246] FIG. 5 shows that the AMPA/kainate receptor antagonist MPQX reduces the severity of paralysis during EAE. MPQX (10 mg/kg i.p. twice daily; 10-16 dpi) significantly reduces the peak disease score. Data represents the mean±sem of disease score, standardised to days after disease onset (&Circlesolid; Vehicle n=26; ◯ MPQX n=12).
[0247] FIG. 6 shows that the non-competitive AMPA antagonist GYKI52466 reduces the severity of paralysis during EAE. GYKI52466 (30 mg/kg i.p. twice daily; 10-16 dpi) significantly reduces the peak disease score. Data represents the mean±sem of disease score, standardised to days after disease onset (Vehicle n=15; 0 GYKI52466 n=16).
[0248] FIG. 7 shows that the non-competitive AMPA antagonist BIIR561 redcues the severity of paralysis during EAE. BIIR561 (30 mg/kg i.p. twice daily; 10-16 dpi) significantly reduces the peak disease score. Data represents the mean±sem of disease score, standardised to days after disease onset (&Circlesolid;Vehicle n=15; ◯BIIR561 n=16).
[0249] FIG. 8 shows that the non-competitive AMPA antagonist CP465022 reduces the severity of paralysis during EAE. CP465022 (10 mg/kg i.p. twice daily; 10-16 dpi) significantly reduces the peak disease score. Data represents the mean±sem of disease score, standardised to days after disease onset (&Circlesolid;Vehicle n=9; ◯CP465022 n=9).
EXAMPLES[0250] Experimental allergic encephalomyelitis (EAE), an inducible autoimmune disease, represents the best characterized animal model of a demyelinating disorder and drugs active in this model proved to be active in humans (Pender MP (1996). Experimental autoimmune encephalomyelitis, In Autoimmune Neurological Disease, Editors Pender UT and McCombe PA, Cambridge University Press. pp 26-88).
[0251] Here we describe a surprising observation on the reduction in neurological deficits during acute EAE in rats following treatment with a non-immunomodulatory and non-antinflamatory agent, the AMPA receptor antagonists, 2,3-dihydroxynitro-7-sulfamoylbenzo-(F)quinoxaline (NBQX). Furthermore, the non-competitive AMPA antagonists (−) 1-(4-aminophenyl)-4methyl-7,8-methylenedioxy-4,5-dihydro-3-methylcarbamoyl-2,3-benzodiazepine (GYKI53773), 1-(-aminophenyl)4methyl-7,8-methylene-dioxy-5H-2,3-benzodiazepine (GYKM52466), 5-(2-[N,N-dimethylamino]oxy-phenyl)-3-phenyl-1,2,4-oxadiazol (BIIR561) and 3-(2-chlorophenyl)-2-[2-[6-[(diethylamino)methyl]-2-pyridinyl]ethenyl]-6-fluoro-4(3H)-quinazolinone (CP465022), and the AMPA/kainate receptor antagonist [1,2,3,4-tetrahydro-7-morpholinyl-2,3-dioxo-6-(trifluoromethyl)quinoxalin-1-yl]methylphosphonate (MPQX) reduced neurological deficits during acute EAE. In addition we also describe the reduction in neurological deficit during chronic EAE in mice following treatment with NBQX.
[0252] Animals
[0253] Female Lewis rats (205+10 g) obtained from Charles River, Kent, UK, were housed in pairs under environmentally controlled conditions (6:00 a.m.-6:00 p.m. light/dark cycle; 22-24° C.; 45-55% humidity) and allowed free access to food and water. Experimental groups consisted of 10 animals. Female Biozzi mice (20±5 g) obtained from Harlan, UK, were housed under the conditions described above. Experimental groups consisted of 7-10 animals.
[0254] Induction of Acute-Active EAE in Lewis Rats
[0255] Rats were immunised in each hind foot with 50 &mgr;l of inoculum containing 50 &mgr;g guinea pig myelin basic protein (MBP, prepared by the method of Dunkley and Carnegie (1974); final concentration 2 mg/ml), emulsified in Freund's complete adjuvant (CFA; Sigma, UK) containing Mycobacterium tuberculosis H37Ra (final concentration 5.5 mg/ml; Difco Laboratories, UK).
[0256] Assessment of Clinical EAE in Lewis Rats
[0257] Animals were weighed and monitored daily and clinical disease scored as (O) no clinical signs; (1) flaccid tail and weight loss; (2) hind limb hypotonia with further weight loss; (3) complete hind limb paralysis; (4) paraplegia and (5) death. In addition, intermediate scores were assigned to animals which showed a loss of tonicity in the distal half of the tail. (score=0.5), paralysis of one hind limb (score=2.5) or complete hind limb paralysis with forelimb weakness (score=3.5). During the period of compound administration (10-16 days post immunisation; dpi) animals were scored 15h after injection of vehicle or NBQX to avoid any acute effect of treatment on disease score.
[0258] Induction of Chronic-Active EAE in Biozzi Mice
[0259] Spinal cords from Biozzi mice (Ab/H, H-2dql) were homogenised and freeze dried. Lyophilised spinal cord homogenate was reconstituted in phosphate buffered saline to a final concentration of 6.6 mg/ml. Incomplete Freund's adjuvant (IFA, Difco) was supplemented with M. tuberculosis (H37Ra, Difco) and M. butyricum (8:1). Biozzi mice were immunised subcutaneously on day 0 and day 7 in the flank at three sites with 0.3 ml of the emulsion (1 mg spinal cord homogenate, 60 &mgr;g of combined M. tuberculosis and butyricum). In addition, mice were injected i.p. with 200 ng of pertussis toxin (Bordetella pertussis, Calbiochem; 2 g/ml in phosphate buffered saline) immediately and 24 h after immunisation with neuroantigens.
[0260] Assessment of Clinical EAE in Biozzi Mice
[0261] Monitoring of neurological deficits was performed daily by blinded observer before administration of vehicle or drugs. The following scoring system was used to grade neurological impairment: (0) no detectable changes; (1) flaccid tail; (2) impairment of righting reflex and/or loss of muscle tone; (3) complete hind limb paralysis; (4) paraplegia; and (5) death. During the period of compound administration (10-16 dpi or 2642 dpi) animals were scored 15h after injection of vehicle of NBQX to avoid any acute effect of treatment on disease score.
[0262] NBQX Administration Regime
[0263] NBQX was initially dissolved in NaOH and diluted with water. pH was adjusted with HCl. Rats were injected i.p. twice daily (9 a.m. and 5 p.m.) on days 10 to 16 post immunisation with either vehicle or NBQX in the dose of 30 mg/kg. Mice were injected i.p. either twice daily (9 a.m. and 5 p.m.) on days 10 to 16 post immunisation or once daily (9 a.m.) on days 26 to 42 post immunisation with either vehicle or NBQX in the dose of 30 mg/kg.
[0264] GYKI53 773 Administration Regime
[0265] GYKI53773 was suspended in 5% cremophore in saline. Rats were injected i.p. twice daily (9 a.m. and 0.5 p.m.) on days 10 to 16 post immunisation with either vehicle or GYKI53773 in the dose of 30 mg/kg.
[0266] GYKI52466 Administration Regime
[0267] GYKI52466 was suspended in 5% cremophore in water. Rats were injected i.p. twice daily (9 a.m. and 5 p.m.) on days 10 to 16 post immunisation with either vehicle or GYKM52466 in the dose of 30 mg/kg.
[0268] BIIR561 Administration Regime
[0269] BIIR561 was suspended in 5% cremophore in water. Rats were injected i.p. twice daily (9 a.m. and 5 p.m.) on days 10 to 16 post immunisation with either vehicle or BIIR561 in the dose of 30 mg/kg.
[0270] CP465022 Administration Regime
[0271] CP465022 was suspended in 5% cremophore in water. Rats were injected i.p. twice daily (9 a.m. and 5 p.m.) on days 10 to 16 post immunisation with either vehicle or CP465022 in the dose of 10 mg/kg.
[0272] MPQX Administration Regime
[0273] MPQX was initially dissolved in NaOH and diluted with water. pH was adjusted with HCl. Rats were injected i.p. twice daily (9 a.m. and 5 p.m.) on days 10 to 16 post immunisation with either vehicle or MPQX in the dose of 10 mg/kg.
[0274] Results
[0275] Effect of NBQX on Disease Progression During EAE in the Lewis Rat
[0276] Following immunisation with MBP, neurological deficit developed in 10/10 vehicle treated animals, 8 of which displayed paralysis of one or both hind limbs; the mean disease onset and duration were 11.8 dpi and 4.7 dpi respectively (FIG. 1 and Table 1). Twice daily treatment from day 10 to 16 post immunisation with NBQX completely prevented the development of paralysis in 6 out of 10 rats, whilst one animal exhibited loss of tone in the most proximal part of the tail (score 0.25) for one day only. The remaining 3 rats displayed paresis of score 1, 2.5 and 3, the onset and duration of which were similar to vehicle injected animals. Thus NBQX significantly reduced disease duration (p<0.001), and peak and cumulative disease score (p<0.01) relative to vehicle treatment. NBQX also conferred protection on weight loss, significantly delaying the onset until 13 dpi (p<0.01) and decreasing the percent body weight lost at the cessation of NBQX administration (day 16; FIG. 2 and Table 1). 1 TABLE 1 Parameters of disease activity during Lewis rat acute EAE Incidence aOnset Duration Peak Disease bCumulative cWeight Treatment (%) (d.p.i.) (days) Score Disease Score Loss (%) Vehicle 10/10 (100) 11.8 (11-14) 4.7 (4-5) 2.7 (2-3.25) 9.8 (5.5-13) 18 (12-23) NBQX 4/10 (75) 11.8 (11-12) 1.5 (0-5)†† 0.7 (0-3)† 2.4 (0-11.5)† 14 (5-20)* Values in the table represent the mean and range where n = 10; *p < 0.05, p < 0.01 and p < 0.001 vs vehicle, Student t-test or Mann-Whitney U-test for parametric and non-parametric data respectively. an = 4 for NBQX. bCumulative disease score calculated by summation of individual daily disease scores. cCalculated as the weight on cessation of treatment (16 dpi) expressed as a percent of the maximum weight before disease onset.
[0277] Effect of GYKI53773 on Disease Progression During EAE in the Lewis Rat
[0278] Following immunisation with MBP, neurological deficit developed in 8/9 vehicle treated animals; the mean disease onset and duration were 11.9 dpi and 3.8 days respectively (FIG. 3 and Table 2). Twice daily treatment from day 10 to 16 post immunisation with GYKI53773 significantly reduced disease duration (p<0.05) and peak and cumulative disease score (p<0.01) relative to vehicle treatment. 2 TABLE 2 Parameters of disease activity during Lewis rat acute EAE. Incidence aOnset Duration Peak Disease bCumulative cWeight Treatment (%) (d.p.i) (days) Score Disease Score Loss (%) Vehicle 8/9 (89) 11.9 (10-16) 3.8 (0-5) 2.6 (0-3.5) 9.5 (0-14.75) 19 (7-26) GYKI53773 6/10 (60) 12.7 (11-14) 1.9 (0-5)* 0.9 (0-2.25)† 2.1 (0-6)† 16 (11-20) Values in the table represent the mean and range where n = 10; *p < 0.05, and †p < 0.01 vs vehicle, Student t-test or Mann-Whitney U-test for parametric and non-parametric data respectively. an = 6 for GYKI53773. bCumulative disease score calculated by summation of individual daily disease scores. cCalculated as the weight on cessation of experiment (20 dpi) expressed as a percent of the maximum weight before disease onset.
[0279] Effect of NBQX on Disease Progression During Chronic EAE in the Biozzi Mouse
[0280] To determine whether AMPA receptor antagonists affect the clinical outcome of chronic EAE, NBQX was administered i.p. to immunised mice. Treatment with NBQX, 30 mg/kg twice daily for 7 days staring on dpi 10, improved neurological outcome reducing disease severity between dpi 10 to 48 [F(1,38)=9.21, P<0.001] (FIG. 4A). Treatment with NBQX, 30 mg/kg once daily for 17 days commencing on dpi 26 also reduced disease severity between dpi 28 to 48 [F(1,20)=2.76, P<0.05] (FIG. 4B).
[0281] Effect of MPQX on Disease Progression During EAE in the Lewis Rat
[0282] Following immunisation with MBP, neurological deficit developed in 26/26 vehicle treated animals; the mean disease onset and duration were 11.2 dpi and 4.8 days respectively (FIG. 5 and Table 3). Twice daily treatment from day 10 to 16 post immunisation with MPQX significantly delayed disease onset (p<0.05), reduced disease duration (p<0.001) and peak and cumulative disease score (p<0.001) relative to vehicle treatment. 3 TABLE 3 Parameters of disease activity during Lewis rat acute EAE. Incidence aOnset Duration Peak Disease bCumulative cWeight Treatment (%) (d.p.i.) (days) Score Disease Score Loss (%) Vehicle 26/26 11.2 (10-13) 4.8 (3-6) 3.5 (2.5-4) 11.0 (8-14.5) 21 (15-28) (100) MPQX 7/12 (58) 12.3 (11-14)* 1.7 (0-5)†† 1.2 (0-3)†† 3.2 22 (13-30) (0-11.5)†† Values in the table represent the mean and range where n = 10; *p < 0.05 and ††p < 0.001 vs vehicle, Student t-test or Mann-Whitney U-test for parametric and non-parametric data respectively. an = 7 for MPQX. bCumulative disease score calculated by summation of individual daily disease scores. cCalculated as the weight on cessation of experiment (18 dpi) expressed as a percent of the maximum weight before disease onset.
[0283] Effect of GYKI52466 on Disease Progression During EAE in the Lewis Rat
[0284] Following immunisation with MBP, neurological deficit developed in 14/15 vehicle treated animals; the mean disease onset and duration were 11.4 dpi and 4.3 days respectively (FIG. 6 and Table 4). Twice daily treatment from day 10 to 16 post immunisation with GYKI52466 significantly reduced peak and cumulative disease score (p<0.01) relative to vehicle treatment. 4 TABLE 4 Parameters of disease activity during Lewis rat acute EAE. Incidence aOnset Duration Peak Disease bCumulative cWeight Treatment (%) (d.p.i.) (days) Score Disease Score Loss (%) Vehicle 14/15 (93) 11.4 (10-16) 4.3 (0-6) 2.8 (0-3.5) 10.9 (0-14.75) 20 (7-26) GYKI52466 15/16 (60) 11.6 (10-13) 4.0 (0.6) 2.4 (0-3.0)** 8.0 (0-13.75)** 20 (8-26) Values in the table represent the mean and range where n = 10; **p < 0.01 vs vehicle, Mann-Whitney U-test for non-parametric data. an = 15 for GYKI2466. bCumulative disease score calculated by summation of individual daily disease scores. cCalculated as the weight on cessation of experiment expressed as a percent of the maximum weight before disease onset.
[0285] Effect of BIIR561 on Disease Progression During EAE in the Lewis Rat
[0286] Following immunisation with MBP, neurological deficit developed in 14/15 vehicle treated animals; the mean disease onset and duration were 11.4 dpi and 4.3 days respectively (FIG. 7 and Table 5). Twice daily treatment from day 10 to 16 post immunisation with BIIR561 significantly reduced peak (p<0.05) and cumulative disease score (p<0.001) relative to vehicle treatment. 5 TABLE 5 Parameters of disease activity during Lewis rat acute EAE. Incidence aOnset Duration Peak Disease bCumulative cWeight Treatment (%) (d.p.i.) (days) Score Disease Score Loss (%) Vehicle 14/15 (93) 11.4 (10-16) 4.3 (0-6) 3.5 (0-3.5) 10.9 (0-14.75) 20 (7-26) BIIR561 16/16 (100) 12.4 (11-19) 3.9 (1-5)†† 2.6 (0.5-3.25)* 7.8 (0.5-11.5)† 17 (5-23)* Values in the table represent the mean and range where n = 10; *p < 0.05 and †p < 0.001 vs vehicle, Student t-test or Mann-Whitney U-test for parametric and non-parametric data respectively. an = 16 for BIIR561. bCumulative disease score calculated by summation of individual daily disease scores. cCalculated as the weight on cessation of experiment expressed as a percent of the maximum weight before disease onset.
[0287] Effect of CP465022 on Disease Progression During EAE in the Lewis Rat
[0288] Following immunisation with MBP, neurological deficit developed in 9/9 vehicle treated animals; the mean disease onset and duration were 10.6 dpi and 5.1 days respectively (FIG. 8 and Table 6). Twice daily treatment from day 10 to 16 post immunisation with CP465022 significantly delayed disease onset (p<0.01), reduced disease duration (p<0.05), peak and cumulative disease score (p<0.01) relative to vehicle treatment. 6 TABLE 6 Parameters of disease activity during Lewis rat acute EAE. Peak Incidence aOnset Duration Disease bCumulative cWeight Treatment (%) (d.p.i) (days) Score Disease Score Loss (%) Vehicle 9/9 (100) 10.6 (10-16) 5.1 (4-6) 3.5 (3.0-3.5) 12.8 (11.75-14.25) 23 (18-26) CP465022 8/9 (89) 13.4 (11-17)** 3.4 (0-5)* 2.0 (0-3.0)** 7.2 (0-13.5)** 20 (10-28) Values in the table represent the mean and range where n = 10; *p < 0.05 and **p < 0.01 vs vehicle, Student t-test and Mann-Whitney U-test for parametric and non-parametric data respectively. an = 8 for CP465022. bCumulative disease score calculated by summation of individual daily disease scores. cCalculated as the weight on cessation of experiment expressed as a percent of the maximum weight before disease onset.
General Remarks[0289] The foregoing description of the invention is merely illustrative thereof and it should therefore be appreciated that various variations and modifications can be made without departing from the spirit or scope of the invention as set forth in the accompanying claims.
[0290] Where preferred or optional features are described in connection with particular aspects of the present invention, they shall be deemed to apply mutatis mutandis to other aspects of the invention unless the context indicates otherwise.
[0291] All documents cited herein are hereby incorporated by reference, as are any citations referred to in said documents.
Claims
1-20. (canceled)
21. A method of treating a demyelinating disorder comprising administering an effective amount of an inhibitor of the interaction of glutamate with the &agr;-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptor complex.
22. The method of claim 21, wherein the demyelinating disorder is acute disseminated encephalomyelitis, acute demyelinating polyneuropathy (Guillain Barre syndrome), chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, Marchifava-Bignami disease, central pontine myelinolysis, Devic syndrome, Balo disease, HIV- or HTLV-myelopathy, progressive multifocal leucoencephalopathy, or a secondary demyelinating disorder.
23. The method of claim 22, wherein the secondary demyelinating disorder is CNS lupus erythematodes, polyarteriitis nodosa, Sjögren syndrome, sarcoidosis or isolated cerebral vasulitis.
24. The method of claim 21, wherein the inhibitor is an antagonist of the binding of glutamate to the AMPA receptor.
25. The method of claim 21, wherein the inhibitor is an L-glutamate derivative, an &agr;-amino-3-hydroxy-5-methyl-4-isoxazolepropionate derivative, arylthioxaline, acid amide, hydrazone, quinoline, quinolinone, quinoxaline, quinoxalinedione, triazoloquinoxalinedione, pyrrolylquinoxalindione, quinazolinone, quinazolinedione, quinoxalinone, phenylpyridazinoindoledione, indenopyrazinone, imidazoloquinoxalinone, indolo-pyrazinone, imidazo-pyrazinone, triazolo-pyrazinone, benzothiadiazine, 4-hydroxypyrrolone, pyrrolo-pyridazinone, phthalazine, quinolone, amino-alkanoic acid, isatine, phenyl-azolophthalazine, amino- or desamino-2,3benzodiazepine, &bgr;-carboline-3-carboxylic acid, alkoxy-phenyl-benzodiazepine, isoquinolinyl-carboxylic acid derivatives, acetyl-aminophenyl-dihydro-methyl-dioxolo-benzodiazepine, pyrimidinone, oxadiazol, isatinoxime, decahydroisoquinoline, piperazine derivative, tetramic acid derivatives, or a sulphamate.
26. The method of claim 21, wherein the inhibitor is L-glutamic acid diethylester, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX), 6,7-dinitro-quinoxaline-2,3-dione (DNQX), 6-nitro-7-cyano-quinoxaline-2,3-dione (CNQX), 6-(1-imidazolyl)-7-nitro-quinoxaline-2,3(1H,4H)-dione (YM90K), (3RS,4aRS,6RS,8aRS)-6-(2-(1H-tetrazole-5-yl)ethyl)-decahydroiso-quinoline-3-carboxylic acid (LY293558), 9-methyl-amino-6-nitro-hexahydro-benzo(F) quinoxalinedione (PNQX), 8-methyl-5-(4-(N,N-dimethylsulphamoyl)phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,2h]-isoquinoline-2,3-dione-3-O-(3-hydroxybutyric acid-2-yl)oxime (NS 1209), 6,7-dichloro-2-(IH)-quinolinone-3-phosphonate (S 17625-2), and [1,2,3,4-tetrahydro-7-morpholinyl-2,3-dioxo-6-(trifluoromethyl)quinoxalin-1-yl]methyl-phosphonate (ZK200775), 1-(4-aminophenyl)-4-methyl-7,8-methylene-dioxy-5H-2,3-benzodiazepine (GYKI52466), (−)1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-4,5-dihydro-3-methylcarbamoyl-2,3-benzodiazepine (GYKI53773), topiramate, 3-(2-chlorophenyl)-2-[2-[6-[(diethylamino)methyl-2-pyridinyl]ethenyl]-6-fluoro-4(3H)-quinazolinone (CP465022) and 5-(2-[N,N-dimethylamino]oxy-phenyl)-3-phenyl-1,2,4-oxadiazol (BIIR561).
27. The method of claim 21, wherein the inhibitor is an AMPA receptor channel blocker.
28. The method of claim 27, wherein the AMPA receptor channel blocker is fluorowillardiine or Joro spider toxin.
29. A method of treating a demyelinating disorder comprising administering a combination of an effective amount of an inhibitor of the interaction of glutamate with the &agr;-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptor complex combined with one or more agents selected from the group consisting of an immunosuppressive agent an interferon (IFN), a phosphodiesterase type IV inhibitor, a humanised monoclonal antibody against a leukocyte adhesion molecule, a synthetic polypeptide, a tissue matrix metalloproteinase (MMP) inhibitor, and a tumour necrosis factor (TNF) inhibitor.
30. The method of claim 29, wherein said combination is administered simultaneously, separately or sequentially.
31-37. (canceled)
38. A pharmaceutical composition for treating a demyelinating disorder comprising an inhibitor of the interaction of glutamate with the &agr;-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptor complex and a pharmaceutically acceptable carrier, wherein the inhibitor is combined with one or more agents selected from the group consisting of an immunosuppressive agent, an interferon (IFN), a phosphodiesterase type IV inhibitor, a humanised monoclonal antibody against a leukocyte adhesion molecule, a synthetic polypeptide, a tissue matrix metalloproteinase (MMP) inhibitor, and a tumour necrosis factor (TNF) inhibitor.
Type: Application
Filed: Dec 22, 2000
Publication Date: Oct 14, 2004
Inventors: Lechoslaw Turski (Berlin), Terence Smith (Cambridge)
Application Number: 09746662
International Classification: A61K031/675; A61K039/395;
